Serine threonine kinase (akt) degradation / disruption compounds and methods of use

ABSTRACT

Disclosed herein are serine threonine kinase (AKT) degradation/disruption compounds including an AKT ligand, a degradation/disruption tag, and a linker, and methods of using such compounds in the treatment of AKT-mediated diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation, and claims priority, of U.S. Application No. 16/977,654, tiled Sep. 2, 2020, which is a U.S. National Stage application, and claims priority of International Application No. PCT/US2019/021014, filed Mar. 6, 2019, which claims priority of U.S. Provisional Application No. 62/639,240, filed Mar. 6, 2018. The contents of all of the prior applications are incorporated herein by reference in their entirety,

TECHNICAL FIELD

This disclosure relates to bivalent compounds (e.g., bi-functional small molecule compounds) which degrade and/or disrupt the serine threonine kinase AKT (also known as protein kinase B or PKB), compositions comprising one or more of the bivalent compounds, and to methods of use thereof for the treatment of AKT-mediated disease in a subject in need thereof. The disclosure also relates to methods for designing such bivalent compounds.

BACKGROUND OF THE INVENTION

Significant efforts have been spent attempting to develop small molecule inhibitors of the kinase activity of the serine threonine kinase AKT (also known as protein kinase B or PKB) because over-activation of AKT is frequently associated with many human malignancies, including colon cancer, ovarian cancer, brain cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and gastric carcinomas. In addition to cancer, aberrant AKT activation has been associated with a variety of other severe human diseases, including developmental and overgrowth syndromes, cardiovascular disease, diabetes, inflammatory and autoimmune disorders, and neurological disorders (Manning and Toker, 2017). AKT is encoded by three closely related genes (AKTI (PKB-α), AKT2 (PKB-β), and AKT3 (PKB-γ)) and is the central node of the PI3K-AKT-mTOR signaling pathway. The AKT signaling pathway can be aberrantly activated by multiple mechanisms in cancers, including, e.g., loss of the tumor suppressor PTEN; activating mutations in AKT, the p110α subunit of PI3K, and/or the PIK3CA gene; and/or increased receptor tyrosine kinase signaling.

However, traditional catalytic inhibition of AKT has not been an optimal solution for treating AKT overexpression. For example, although ATP-competitive inhibitors like GDC0068 (Blake et al., 2012) function as pan-AKT inhibitors, they also stabilize AKT in its active conformation, resulting in AKT hyperphosphorylation. Moreover, AKT has functions in addition to the (catalytic) activity targeted by small molecule inhibitors. AKT's kinase-independent functions promote cancer cell survival in a pleckstrin homology (PH)-domain dependent manner. Studies have shown that the enzymatic inhibitor GDC0068 alone was not very effective in a colon cancer xenograft with RAS/RAF activation albeit with PIK3CA mutation. Similarly, GDC0068 also failed to result in significant objective tumor shrinkage in a phase I clinical trial (Saura et al., 2017).

Unlike traditional enzyme inhibitors, which only inhibit the catalytic activity of the target enzyme, the AKT degradation/disruption compounds (“AKT degraders”) disclosed herein bind and induce degradation of AKT, thus eliminating any scaffolding functions of AKT in addition to eliminating its enzymatic activity. The AKT degraders disclosed herein are bivalent compounds, including an AKT ligand conjugated to a degradation/disruption tag via a linker.

The AKT degraders disclosed herein offer a novel mechanism for treating AKT-mediated diseases. In particular, the ability of the AKT degraders to target AKT for degradation, as opposed to merely inhibiting AKT's catalytic activity, is expected to overcome resistance, regardless of whether specific drugs were used in a prior treatment and regardless of whether the resistance is caused by gene mutation, amplification, or otherwise.

In an aspect, this disclosure provides a method of treating AKT-mediated diseases, the method including administering one or more AKT degraders to a subject who has an AKT-mediated disease, the AKT degraders being bivalent compounds including an AKT ligand conjugated to a degradation/disruption tag via a linker. The AKT-mediated disease can be a disease resulting from AKT activation. The AKT-mediated disease can have elevated AKT enzymatic activity relative to a wild-type tissue of the same species and tissue type. Non-limiting examples of AKT-mediated diseases include inflammatory, hyperproliferative cardiovascular, neurodegenerative, gynecological, and dermatological diseases and disorders.

In an aspect, the AKT degraders of the present disclosure can be employed for the treatment of hyperproliferative disorders, including cancers angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, leiomyosarcoma, stomach carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenotna, villous adenoma, hamartoma, kidney cancer, Wilm's tumor, nephroblastoma, leukemia, bladder cancer, urethra cancer, transitional cell carcinoma, prostate cancer, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, osteogenic sarcoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, osteoma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, endometrial carcinoma, cervical carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, intraepithelial carcinoma, melanoma, clear cell carcinoma, botryoid sarcoma, embryonal fallopian tubes carcinoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, advanced melanoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, angioma, dermatofibroma, keloids, psoriasis, neuroblastoma, metastatic breast cancer, colon cancer, oral cancer, hairy cell leukemia, head and neck cancer, refractory metastatic disease; Kaposi's sarcoma, Bannayan-Zonana syndrome, Cowden disease and Lhermitte-Duclos disease.

The compounds and methods of this disclosure can be also used to treat diseases and conditions such as rheumatoid arthritis, osteoarthritis. Crohn's disease, angiofibroma, retinal vascularization, diabetic retinopathy, age-related macular degeneration, macular degeneration, multiple sclerosis, obesity, Alzheimer's disease, restenosis, autoimmune diseases, allergy, asthma, endometriosis, atherosclerosis, vein graft stenosis, peri-anastomatic prosthetic graft stenosis, prostate hyperplasia, chronic obstructive pulmonary disease, psoriasis, inhibition of neurological damage due to tissue repair, scar tissue formation, multiple sclerosis, inflammatory bowel disease, infections, particularly bacterial, viral, retroviral or parasitic infections, pulmonary disease, neoplasm, Parkinson's disease, transplant rejection, and septic shock.

The AKT-mediated disease can be a relapsed disease. The AKT-mediated disease can have been refractory to one or more previous treatments by different therapies.

SUMMARY OF THE INVENTION

The present disclosure relates generally to bivalent compounds (e.g., bi-functional compounds) which degrade and/or disrupt AKT, and to methods for the treatment of AKT-mediated cancer (i.e., a cancer which depends on AKT protein; or cancer having elevated levels of AKT, or AKT activity relative to a wild-type tissue of the same species and tissue type). Because the AKT degraders/disruptors have dual functions (enzyme inhibition plus protein degradation/disruption), the bivalent compounds of the present disclosure can be significantly more effective therapeutic agents than current AKT inhibitors, which inhibit the enzymatic activity of AKT, but do not affect AKT protein levels. The present disclosure further provides methods for identifying AKT degraders/disruptors as described herein.

More specifically, the present disclosure provides a bivalent compound including an AKT ligand conjugated to a degradation/disruption tag via a linker.

In some aspects, the AKT deeraders/disruptors have the form “PI-Linker-EL”, as shown below:

wherein PI (a ligand for a “protein of interest,” i.e., the protein to be degraded) comprises an AKT ligand (e.g., an AKT inhibitor), and EL (e.g., a ligand for an E3 ligase) comprises a degradation/disruption tag (e.g., E3 ligase ligand). Exemplary AKT ligands (PI), exemplary degradation/disruption tags (EL), and exemplary linkers (Linker) are illustrated below:

AKT Ligands

AKT Ligands include but are not limited to:

wherein

A, B, and X are independently N, CH, or CR⁶,

Y is CH₂, CO, SO, SO₂, CR⁷R⁸, CONR⁷, or SO₂NR⁷,

E is NH, NR⁹, O, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkvl, C₁-C₈ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₇ heterocyclyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, OR⁹, SR⁹, NR⁹R¹⁰, CN, NO₂, (CR⁹R¹⁰)mNR¹¹R¹², (CR⁹R¹⁰)mC(O)R¹¹, (N R⁹R¹⁰)mNR¹¹R¹², (NR⁹R¹⁰)mC(O)R¹¹, COR⁹, CO₂R⁹, CONR⁹R¹⁰, NR⁹COR¹⁰, NR⁹SOR¹⁰, NR⁹SOR₂R¹⁰, SOR⁹, SO₂R⁹, SO₂NR⁹R¹⁰, (CR⁹R¹⁰)m-aryl, or (CR⁹R¹⁰)m-heteroaryl,

R¹ is H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, aryl, C₁-C₈ alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,

R², R³, R⁴, and R⁶ are independently hydrogen, halogen, amino, C₁-C₈ alkylamino, arylamino, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkoxyakl,

R⁵, R⁷, and R⁸ are independently H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, or C₁-C₈ alkoxyalkyl;

R⁹, R¹⁰, R¹¹, and R¹² are independently H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₂-C₈ alkenyl, C₂-C₈ alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl,

R⁹ and R¹⁰, R¹¹ and R¹² can independently form 4-8 membered alkyl or heterocyclyl rings, m=0-8;

and

n=0-8; and

wherein

A, B and X are independently selected from d CR⁶, wherein

R⁶ is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylamino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

Y is selected from CR⁷R⁸, CO, SO, SO₂, CONR⁷, and SO₂NR⁷, wherein

R⁷ and R⁸ is independently selected from hydrogen, halogen, optionally substituted C₁-C₈ alkyl, optionally substituted. C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl; optionally substituted C₁-C₈ alkylamino, optionally substituted C₁-C₈ alkylamino C₁-C₈ alkyl, optionally substituted 3 to 10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, or

R⁷ and R⁸ together with the atom to which they are connected form an optionally substituted 3-10 membered carbocyclyl or an optionally substituted 4-10 membered heterocyclyl ring;

E is connected to the “linker” moiety of the bivalent compound, and is selected from null, R′—R″R′OR″, R′SR″, R′NR⁹R″, R′OC(O)R″, R′OC(O)OR″, R′OCONR⁹R″, R′C(O)R″, R′C(O)OR″, R′CONR⁹R″, R′S(O)R″, R′S(O)₂R″, R′SO₂NR⁹R″, R′NR¹⁰C(O)OR″, R′NR¹⁰C(O)R″, R′NR¹⁰C(O)NR⁹R″, R′NR¹⁰S(O)R″, R′NR¹⁰S(O)₂R″, and R′NR¹⁰S(O)₂NR⁹R″, wherein

R′ and R″ are independently selected from null, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-ColkoxyC₁-C₈alkyl optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ alkynylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted (C₁-C₈ aklene)O(C₁-C₈ alkylene), optionally substituted (C₁-C₈ alkylene)N(C₁-C₈ alkylene), optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused carbocyclyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridged carbocyclyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro carbocyclyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁹ and R¹⁰ 0 are independently selected from hydrogen, optionally substituted. C₁-C₈ optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈ alkyl, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R⁹ and R¹⁰, R′ and R⁹, R′ and R¹⁰, R″ and R⁹, R″ and R¹⁰ together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

R¹ is selected from hydrogen, halogen, and optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted C₁-C₈ alkylamino, optionally substituted C₁-C₈ alkylamino C₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroalyl,

R², R³ and R⁴ are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted aryloxy, optionally substituted C₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted amino, optionally substituted C₈ alkylamino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted arylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

R⁵ is selected from hydrogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl; and

In one embodiment, A is selected from N, CH and CNH2.

In another embodiment, A is N.

In one embodiment, B and X are independently selected from N and CH.

In another embodiment, B is N.

In another embodiment, X is N.

In another embodiment, Y is selected from CH₂, CO, CONH and NHCO.

In another embodiment, Y is CO.

In another embodiment, E is selected from null, O, N, optionally substituted C₁-C₈ alkylene, optionally substituted (C₁-C₈ alkylene)O, optionally substituted (C₁-C₈ alkylene)N, optionally substituted 3-10 membered carbocyclylene, optionally substituted (3-10 membered carbocyclylene)O, optionally substituted (3-10 membered carbocyclylene)N, optionally substituted 4-10 membered heterocyclylene, optionally substituted (4-10 membered heterocyclyiene)O, optionally substituted (4-10 membered heterocyclylene)N, optionally substituted aryl, and optionally substituted heteroaryl.

In another embodiment, R¹ is selected from optionally substituted aryl and optionally substituted heteroaryl.

In another embodiment, R¹ is selected from optionally substituted phenyl.

In another embodiment, R¹ is 4-chlorophenyl.

In another embodiment, R², R³, R⁴ and R⁵ are independently selected from H, F, ClCN, NO₂, CH₃, CF₃, iPr, and cPr.

In another embodiment, R², R⁴ and R⁵ are H.

In another embodiment, R³ is CH₃.

wherein

A, B, and X are independently N or CR³,

Y is CH₂, CO, SO, SO₂, CR⁴R⁵, CONR⁴, or SO₂NR⁴,

E is NH, NR⁶, O, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, SR⁶, NR⁶R⁷, CN, NO₂, (CR⁶R⁷)mNR⁸R⁹, (CR⁶R⁷)mC(O)R⁸, (N R⁶R⁷)mNR⁸R⁹, (NR⁶R⁷)mC(O)R⁸, COR⁶, CO₂R⁶, CONR⁶R⁷, NR⁶COR⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, SOR⁶, SO₂R⁶, SO₂NR⁶R⁷, (CR⁶R⁷)m-aryl, or (CR⁶R⁷)m-heteroaryl,

Z¹-Z² is CR¹⁰═CH, N+CH, or CR¹⁰═N,

R¹ is hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, aryl, C₁-C₈ alkylaryl, haloaryl, arylalkyl, heteroarvl, or heteroarylalkyl,

R², R³, and R⁴ are independently hydrogen, halogen, amino, C₁-C₈ alkylamino, arylamino, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkoxyalkyl,

R⁶, R⁷, R⁸, and R⁹ are independently H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₂-C₈ alkenyl, C₂-C₈ alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl,

R⁶ and R⁷, R⁸ and R⁹ can independently form 4-8 membered alkyl or heterocyclyl rings,

R¹⁰ is hydrogen, halogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl,

m=0-8,

and

n=0-8.

wherein

A, B and X are independently selected from N and CR³, wherein

R³ is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylamino C₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

Z¹ is selected for CR⁸ and N, wherein

R⁸ is selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

Z² is selected for CH and N;

Y is selected from CO, SO, SO₂, CR⁴R⁵, CONR⁴, and SO₂NR⁴, wherein

R⁴ and R⁵ is independently selected from hydrogen and optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3 to 10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

E is connected to the “linker” moiety of the bivalent compound, and is selected from null, R″, R′OR″, R′SR″, R′NR⁶R″, R′OC(O)R″, R′OC(O)OR″, R′OCONR⁶R″, R′C(O)R″, R′C(O)OR″, R′CONR⁶R″, R′S(O)R″, R′S(O)₂R″, R′SO₂NR⁶R″, R′NR⁷C(O)OR″, R′NR⁷C(O)R″, R′NR⁷C(O)NR⁶R″, R′NR⁷S(O)R″, R′NR⁷S(O)₂R″, and R′NR⁷S(O)₂NR⁶R″, wherein

R′ and R″ are independently selected form null, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkoxy C₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ alkynylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted (C₁-C₈ alkylene)O(C₁-C₈ alkylene), optionally substituted (C₁-C₈ alkylene)N(C₁-C₈ alkylene), optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused carbocyclyl, optionally substituted C₁-C₈ 3-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridged carbocyclyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro carbocyclyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁶ and R⁷ are independently selected from hydrogen, optionally substituted C₁-C₈ optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R′ and R″, R⁶ and R⁷, R′ and R⁶, R′ and R⁷, R″ and R⁶, R″ and R⁷ together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

R¹ is selected from selected from hydrogen, halogen, and optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ optionally substituted C₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryt and

R² is selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, or optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylaminoCt-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

In one embodiment, A is selected from N, CH and CNH₂.

In another embodiment, A is CNH₂.

In one embodiment, B and X are independently selected from N and CH.

In another embodiment, B is N.

In another embodiment, X is N.

In another embodiment, Z¹ s selected from CH and CCH₃.

In another embodiment, Z¹ is CH.

In another embodiment, Z² is CR

In another embodiment, Y is selected from CH₂, CO, CONH and NHCO.

In another embodiment, Y is CONH.

In another embodiment, E is selected from null, O, N, optionally substituted C₁-C₈ alkylene, optionally substituted (C₁-C₈ alkylene)O, optionally substituted (C₁-C₈ alkylene)N, optionally substituted 3-10 membered carbocyclylene, optionally substituted (3-10 membered carbocyclyiene)O, optionally substituted (3-10 membered carbocyclylene)N, optionally substituted 4-10 membered heterocyclylene, optionally substituted (4-10 membered heterocyclylene)O, optionally substituted (4-10 membered heterocyclylene)N, optionally substituted aryl, and optionally substituted heteroaryl.

In another embodiment, R¹ is selected from optionally substituted aryl and optionally substituted heteroaryl.

In another embodiment, R¹ is selected from optionally substituted phenyl.

In another embodiment, R¹ is 4-chlorophenyl.

In another embodiment, R² is selected from H, F Cl, CN, NO₂, CH₃, CF₃, iPr, and cPr,

In another embodiment, R² is H.

The AKT ligand can be an AKT inhibitor, such as, for example, GSK_690693 (Heerding et al., 2008), GSK2110183 (Dumble et al., 2014), GSK2141795 (Dumble et al., 2014), AZD5363 (Addie et al., 2013), GDC0068 (Blake et al., 2012), MK-2206 (Hirai et al., 2010), and ARQ-092 (Yu et al., 2015), and/or analogs thereof,

In some aspects, the AKT ligand can be, e.g.:

The AKT ligand can be bound to AKT and/or AKT mutant proteins, such as, e.g., AKT with an E17K mutation.

Degradation/Disruption Tats

Degradation/Disruption Tags (EL) include but are not limited to:

wherein

V, W, and X are independently CR² or N,

Y is CO or CH₂,

Z is CH₂, NH, or O,

R¹ is hydrogen, methyl, or fluoro, and

R² is hydrogen, halogen, or C₁-C₅ alkyl;

wherein

V, W, and X are independently selected from CR² and N;

Y is selected from CO, CH₂, and N═N;

Z is selected from CH₂, NH and O; and

R¹ and R² are independently selected from hydrogen, halogen, cyano, nitro, and C₁-C₅ alkyl.

wherein

R¹ and R² are independently hydrogen, C₁-C₈ alkyl, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ heterocyclyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl;

wherein

R¹ and Ire are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ aminoalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.

R³ is selected from hydrogen, optionally substituted C(O)C₁-C₈ alkyl, optionally substituted C(O)C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted. C(O)C₁-C₈ haloalkyl, optionally substituted C(O)C₁-C₈ hydroxyalkyl, optionally substituted C(O)C₁-C₈ aminoalkyl, optionally substituted C(O)C₁-C₈alkylaminoCt-C₈alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(O)C₂-C₈ alkenyl, optionally substituted C(O)C₂-C₈ optionally substituted C(O)OC₁-C₈ alkoxyC₁-C₈alkyl, optionally substituted C(O)OC₁-C₈ haloalkyl, optionally substituted C(O)OC₁-C₈ hydroxyalkyl, optionally substituted C(O)OC₁-C₈ aminoalkyl, optionally substituted C(O)OC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC₂-C₈ alkenyl, optionally substituted C(O)OC₂-C₈ alkynyl, optionally substituted C(O)NC₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted C(O)NC₁-C₈ haloalkyl, optionally substituted C(O)NC₁-C₈ hydroxyalkyl, optionally substituted C(O)NC₁-C₈ aminoalkyl, optionally substituted C(O)NC₁-C₈alkylaminoCt-C₈alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC₂-C₈ alkenyl, optionally substituted C(O)NC₂-C₈ alkynyl, optionally substituted P(O)(OH)₂, optionally substituted P(O)(OC₁-C₈ alkyl)₂, and optionally substituted P(O)(OC₁-C₈ aryl)₂. and

wherein

R¹, R², R³, and R⁴ are independently hydrogen, C₁-C₈ alkyl, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ heterocyclyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, and

V, W, X, and Z are independently CR⁴ or N.

wherein

V, W, X, and Z are independently selected from CR⁴ and N; and

R¹, R², R³, and R⁴ are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈ alkynyl; optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclvl.

In some aspects, the degradation/disruption tag can be, for example, pomalidomide (Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide (Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al., 2017), adamantine (Xie et al., 2014), 1-((4.4,5,5,5-pentafluoropentypsulfinyl)nonane (E.Wakeling, 1995), nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG 232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), bestatin (Hiroyuki Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161 (Weisberg et al., 2010), and/or analogs thereof.

In some aspects, the degradation/disruption tag can be, e.g., one of the following structures:

In some aspects, the degradation/disruption tag can bind to a ubiquitin ligase (e.g., an E3 ligase such as a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM21 ligase, a TRIM24 ligase, and/or an IAP ligase) and/or serve as a hydrophobic group that leads to AKT protein misfolding.

Linkers

In all of the above-described compounds, the AKT ligand is conjugated to the degradation/disruption tag through a linker. The linker can include, for example, acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic and/or carbonyl containing groups with different lengths.

In some aspects, the linker can be a moiety of:

wherein

A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR, R′CO₂R″, R′C(O)NR″R¹, R′C(S)NR″R¹, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR¹R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂NR″R¹, R′NR″R¹, R′NR¹COR″, R′NR¹C(O)OR″, R′NR¹CONR″R², R′NR¹C(S)R″, R¹NR¹S(O)R″, R′NR¹S(O)₂R′, and R′NR¹S(O)₂NR²R″, wherein

R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ t-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ 1-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ alkynylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R¹ and R² are independently selected from hydrogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted Cr-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted amyl, and optionally substituted heteroaryl;

R′ and R″, R¹ and R², R′ and R¹, R′ and R², R″ and R¹, R″ and R² together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and

m is 0 to 15.

In one embodiment, the linker moiety is of FORMULA 9A:

wherein

R¹, R², R³ and R⁴, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkylamino, and optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹ and R², R³ and R⁴ together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)NR″R¹, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR¹R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂NR″R¹, R′NR″R¹, R′NR¹COR″, R′NR¹C(O)OR″, R′NR¹CONR″R², R′NR¹C(S)R″, R′NR¹S(O)R″, R′NR¹S(O)₂R″, and R′NR¹S(O)₂NR²R″, wherein

R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ alkynylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted. C₁-C₈ haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₁-C₈ 3-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₁-C₁₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁵ and R⁶ are independently selected from hydrogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted. C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydrovalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl,

R′ and R″, R⁵ and R⁶, R′ and R⁵, R′ and R⁶, R″ and R⁵, R″ and R⁶ together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

m is 0 to 15;

n, at each occurrence, is 0 to 15; and

o is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9B:

wherein

R¹ and R², at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkylamino, C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R′ and R″ together with the atom to which they are connected form a 3-20 mentbered cycloalkyl or 4-20 membered heterocyclyl ring;

A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)NR″R¹, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR¹R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂NR″R¹, R′NR″R¹, R′NR¹COR″, R′NR¹C(O)OR″, R′NR¹CONR″R², R′NR¹C(S)R″, R′NR¹S(O)R″, R′NR¹S(O)₂R″, and R′NR¹S(O)₂NR²R″, wherein

R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted Cr-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈ alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ alkynylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₁-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R³ and R⁴ are independently selected from hydrogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ dlkynyl, optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R³ and R⁴, R′ and R³, R′ and R⁴, R″ and R³, R″ and R⁴ together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

each m is 0 to 15; and

n is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9C:

wherein

X is selected from O, NH, and NR⁷;

R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkylamino, optionally substituted C₁-C₈ alkyl aminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered cycloalkoxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)NR″R¹, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR¹R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂NR″R¹, R′NR″R¹, R′NR¹COR″, R′NR¹C(O)OR″, R′NR¹CONR″R², R′NR¹C(S)R″, R′NR¹S(O)R″, R′NR¹S(O)₂NR²″, and R′NR¹S(O)₂NR²R″, wherein

R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkoxyC₁-C₈alkyl, optionally substituted CA-CgalkylaminoC₁-C₈ alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C,-C₈ alkynylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁸ and R⁹ are independently selected from hydrogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R⁸ and R⁹, R′ and R⁸, R′ and R⁹, R″ and R⁸, R″ and R⁹ together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

m, at each occurrence, is 0 to 15;

n, at each occurrence, is 0 to 15;

o is 0 to 15; and

p is 0 to 15.

In another embodiment, A and B, at each occurrence, are independently selected from null, CO, NH, NH—CO, CO—NH, CH₂—NH—CO, CH₂—CO—NH, NH—CO—CH₂, CO—NH—CH₂, CH₂—NH—CH₂—CO—NH, CH₂—NH—CH₂—NH—CO, —CO—NH, CO—NH—CH₂—NH—CH₂, CH₂—NH—CH₂.

In another embodiment, o is 0 to 5.

In another embodiment, the linker moiety comprises a ring selected from the group consisting of a 3 to 13 membered ring, a 3 to 13 membered fused ring, a 3 to 13 membered bridged ring, and a 3 to13 membered spiro ring.

In another embodiment, the linker moiety comprises one or more rings selected from the group consisting of FORMULAE C1, C2, C3, C4 and C5:

wherein X is C═O or CH₂,

Y is C═O or CH₂, and

n is 0-15;

wherein X is C═O or CH_(2,)

Y is C═O or CH₂,

m is 0-15,

n is 0-6, and

o is 0-15; or

wherein

X is C═O or CH₂,

Y is C═O or CH₂,

R is —CH₂—, —CF₂—, CH(C₁₋₃alkyl)—, —C(C₁₋₃alkyl)(C₁₋₃alkyl)—, —CH═CH—, —C(C₁₋₃ alkyl)═C(C₁₋₃alkyl)—, —C═C—, —O—, —NH—, —N(C₁₋₃alkyl)—, —C(O)NH—, —C(O)N(C₁₋₃ alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring,

m is 0-15, and

n is 0-15.

In some aspects of Formula C, R is a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spino ring, one or more of which can contain one or more heteroatoms.

In some aspects of Formula C, R has a structure of:

In some aspects, the bivalent compound is a compound selected from the following compounds, as identified in Table 1 below: XF038-157A, XF038-158A, XF038-159A, XF038-160A, XF038-161A, XF038-162A, XF038-164A, XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-164, XF042-165, XF042-166, XF042-167, XF042-168, XF042-170, XF042-171, XF048-1, XF048-2, XF048-3, XF048-4, XF048-5, XF048-7, XF048-8, XF050-5, XF050-6, XF050-7, XF050-8, XF050-9, XF050-10, XF050-11, XF050-12, XF050-13, XF050-14, XF050-15, XF050-16, XF050-17, XF050-18, XF050-19, XF050-20, XF050-21, XF050-22, XF050-23, XF050-24, XF050-25, XF050-26, XF050-27, XF050-28, XF050-29, XF050-30, XF050-31, XF050-32, XF050-33, XF050-98, XF050-132, XF050-133. XF050-134, XF056-93, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, XF056-36, XF056-37, XF056-73, XF061-10, XF067-1, XF067-2, XF067-3, XF067-4, XF067-5, XF067-6, XF067-7, XF067-8, XF067-9, XF067-10, XF067-11, XF067-12, XF067-13, XF067-14, XF067-15, XF067-16, XF067-17, XF067-18, XF067-19, XF067-20, XF067-21, XF067-22, XF067-23, XF067-24, XF067-25, XF067-26, XF067-27, XF067-28, XF067-29, XF067-30, XF067-31, XF067-32, XF067-33, XF067-34, XF067-35, XF067-36, XF067-37, XF067-38, XF067-39, XF067-40, XF067-41, XF067-42, XF067-43, XF067-44, XF067-45, XF067-46, XF067-47, XF067-48, XF067-49, XF067-50, XF067-51, XF067-52, XF067-53, XF067-54, XF067-55, XF067-56, XF067-57, XF067-58, XF067-59, XF067-84, XF067-85, XF067-86, XF067-87, XF067-88, XF067-89, XF067-90, XF067-91, XF067-92, XF067-93, XF067-94, XF067-95, XF067-96, XF067-97, XF067-98, XF067-99, XF067-100, XF067-101XF067-102XF067-103XF067-104XF067-105, XF067-106, XF067-107, XF067-108, XF067-109, XF067-110, XF067-111, XF067-112, XF067-113, or analogs thereof.

In some aspects, this disclosure provides a method of treating AKT-mediated cancers, the method including administering to a subject in need thereof one or more bivalent compounds including an AKT ligand conjugated to a degradation/disruption tag via a linker. The AKT-mediated cancer can be a cancer resulting from (aberrant) AKT activation. The AKT-mediated cancer can have elevated AKT enzymatic activity relative to a wild-type tissue of the same species and tissue type. Non-limiting examples of AKT-mediated diseases include inflammatory, hyperproliferative cardiovascular, neurodegenerative, gynecological, and dermatological diseases and disorders. In an aspect, the AKT degraders of the present disclosure can be employed for the treatment of hyperproliferative disorders, including cancers angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, leiomyosarcoma, stomach carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma, carcinoid tumors, K.aposi.'s sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenoma, villous adenoma, hamartoma, kidney cancer, Wilm's tumor, nephroblastoma, leukemia, bladder cancer, urethra cancer, transitional cell carcinoma, prostate cancer, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, osteogenic sarcoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, osteoma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, endometrial carcinoma, cervical carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, gran ulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, intraepithelial carcinoma, melanoma, clear cell carcinoma, botryoid sarcoma, embryonal fallopian tubes carcinoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, advanced melanoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, angioma, dermatofibroma, keloids, psoriasis, neuroblastoma, metastatic breast cancer, colon cancer, oral cancer, hairy cell leukemia, head and neck cancer, refractory metastatic disease; Kaposi's sarcoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease.

The compounds and methods of this disclosure can be also used to treat diseases and conditions such as rheumatoid arthritis, osteoarthritis, Crohn's disease, angiofibroma, retinal vascularization, diabetic retinopathy, age-related macular degeneration, macular degeneration, multiple sclerosis, obesity, Alzheimer's disease, restenosis, autoimmune diseases, allergy, asthma, endometriosis, atherosclerosis, vein graft stenosis, peri-anastomatic prosthetic graft stenosis, prostate hyperplasia, chronic obstructive pulmonary disease, psoriasis, inhibition of neurological damage due to tissue repair, scar tissue formation, multiple sclerosis, inflammatory bowel disease, infections, particularly bacterial, viral, retroviral or parasitic infections, pulmonary disease, neoplasm, Parkinson's disease, transplant rejection, and septic shock,

The AKT-mediated disease can be a relapsed disease. The AKT-mediated disease can have been refractory to one or more previous treatments by different therapies.

In any of the above-described methods, the bivalent compounds can be XF038-157A, XF038-158A, XF038-159A, XF038-160A, XF038-161A, XF038-162A, XF038-164A, XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-164, XF042-165, XF042-166, XF042-167, XF042-168, XF042-170, XF042-171, XF048-1, XF048-2, XF048-3, XF048-4, XF048-5, XF048-7, XF048-8, XF050-5, XF050-6, XF050-7, XF050-8, XF050-9, XF050-10, XF050-11, XF050-12, XF050-13, XF050-14, XF050-15, XF050-16, XF050-17, XF050-18, XF050-19, XF050-20, XF050-21, XF050-22, XF050-23, XF050-24, XF050-25, XF050-26, XF050-27, XF050-28, XF050-29, XF050-30, XF050-31, XF050-32, XF050-33, XF050-98, XF050-132, XF050-133. XF050-134, XF056-93, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, XF056-36, XF056-37, XF056-73, XF061-10, XF067-I, XF067-2, XF067-3, XF067-4, XF067-5, XF067-6, XF067-7, XF067-8, XF067-9, XF067-10, XF067-11, XF067-12, XF067-13, XF067-14, XF067-15, XF067-16, XF067-17, XF067-18, XF067-19, XF067-20, XF067-21, XF067-22, XF067-23, XF067-24, XF067-25, XF067-26, XF067-27, XF067-28, XF067-29, XF067-30, XF067-31, XF067-32, XF067-3 XF067-34, XF067-35, XF067-36, XF067-37, XF067-38, XF067-39, XF067-40, XF067-41, XF067-42, XF067-43, XF067-44, XF067-45, XF067-46, XF067-47, XF067-48, XF067-49, XF067-50, XF067-51, XF067-52, XF 067-53, XF067-54, XF067-55, XF067-56, XF067-57, XF067-58, XF067-59, XF067-84, XF067-85, XF067-86, XF067-87, XF067-88, XF067-89, XF067-90, XF067-91, XF067-92, XF067-93, XF067-94, XF067-95, XF067-96, XF067-97, XF067-98, XF067-99, XF067-100, XF067-101, XF067-102, XF067-103, XF067-104, XF067-105, XF067-106, XF067-107, XF067-108, XF067-109, XF067-110, XF067-111₋XF067-112₋XF067-113, or analogs thereof.

In some aspects of the methods described herein, the bivalent compounds can be administered, e.g., orally, parenterally, intradermally, subcutaneously, topically, and/or rectally.

Any of the above-described methods can further include treating a subject with one or more additional therapeutic regimens for treating cancer. The one or more additional therapeutic regimens for treating cancer can be, e.g., one or more of surgery, chemotherapy, radiation therapy, hormone therapy, or immunotherapy.

This disclosure additionally provides a method for identifying a bivalent compound which mediates degradation/disruption of AKT, the method including providing a heterobifunctional test compound including a AKT ligand conjugated to a degradation/disruption tag via a linker, contacting the heterobifunctional test compound with a cell (e.g., a cancer cell such as a AKT-mediated cancer cell) including a ubiquitin ligase and AKT.

As used herein, the terms “about” and “approximately” are defined as being within plus or minus 10% of a given value or state, preferably within plus or minus 5% of said value or state. The terms “bivalent” and “bi-functional” are used interchangeably herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C are a series of Western blots showing the effect of various AKT degraders on reducing AKT, p-AKT, P-PRAS40 (T246), and P-S6 (S240/244) protein levels at various concentrations in BT474 cells. (Note: “XF” portion of the degrader compound code was omitted).

FIG. 2 is a Western blot showing that XF038-166A time-dependently reduces AKT p-AKT, P-PRAS40 (T246), and P-S6 (S240/244) protein levels in BT474 cells.

FIG. 3A-C are a series of Western blots showing the effect of various AKT degraders on reducing AKT, p-AKT, P-PRAS40 (T246), and P-S6 (S240/244) protein levels at various concentrations in BT474 cells. (Note: “XF” portion of the degrader compound code was omitted)

FIG. 4A is a series of Western blots showing the effect of selected AKT degraders on reducing AKT, p-AKT, P-PRAS40 (T246), and P-S6 (S240/244) protein levels at various concentrations in B1474 cells.

FIG. 4B is a series of Western blots showing the effect of XF050-21 on reducing AKT, p-AKT, P-PRAS40 (T246), and. P-S6 (S240/244) protein levels at various concentrations in PC-3, MDA-MB-468, and U87MG cells.

FIG. 5A is a series of Western blots showing that XF050-21, XF050-33, XF042-162 and XF042-170 time-dependently reduce AKT, p-AKT, P-PRAS40 (T246), and P-S6 (S240/244) protein levels in BT474 cells.

FIG. 59 is a Western blot showing that XF050-21 time-dependently reduces AKT, p-AKT, P-PRAS40 (T246), and P-S6 (S240/244) protein levels in PC3 cells.

FIG. 6 is a Western blot showing the effect of XF050-21 on reducing the AKT and p-AKT levels can be blocked by pretreatment of VHL-1, MLN4924, MG132, and AZD5363 in BT474 cells.

FIG. 7 is a series of concentration-response curves showing that XF050-21 was more effective than AZD5363 in inhibiting cell growth of PC-3 and MDA-MB-468 cells.

FIG. 8A-B are a series of cell culture dish pictures showing that XF050-21 was more effective than AZD5363 in inhibiting colony formation of PC-3, MDA-MB-468, HCC 1143, and MDA-MB-231 cells.

FIG. 9 is a series of Western blots showing the combination effect of an AKT degrader (XF050-21 or XF041-170) with an mTOR inhibitor (Torin1 or Rapamycin) in BT474 cells.

FIG. 10 is the mouse plasma exposure curve of XF050-21.

FIG. 11 is a series of Western blots showing the effect of various AKT degraders on reducing AKT, p-AKT, P-PRAS40 (T246), and P-S6 (S240/244) protein levels at 1 μM compound concentration in PC-3 cells.

FIG. 12 is a series of Western blots showing the effect of various AKT degraders on reducing AKT, p-AKT, P-PRAS40 and P-S6 (S240/244) protein levels at 1 uM compound concentration in PC-3 cells.

DEFINITION OF TERMS

As used herein, the terms “comprising” and “including” are used in their open, non-limiting sense.

“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. An alkyl may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, an alkyl comprises one to fifteen carbon atoms (e.g., C₁-C₁₅ alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C₅-C₈ alkyl). The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methyl ethyl (iso-propyl), n-butyl, n-pentyl, 1.1-dimethylethyl (t-butyl), pentyl, 3-methythexyl, 2-methylhexyl, and the like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond. An alkenyl may comprise two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, an alkenyl comprises two to twelve carbon atoms (e.g., C₂-C₁₂ alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (e.g., C₂-C₈ alkenyl), In certain embodiments, an alkenyl comprises two to six carbon atoms (e.g., C₂-C₆ alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (e.g., C₂-C₄ alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, penta-1,4-dienyl, and the like.

The term “allyl,” as used herein, means a —CH₂CH═CH₂ group.

As used herein, the term “alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond. An alkynyl may comprise two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, an alkynyl comprises two to twelve carbon atoms (e.g., C₂-C₁₂ alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (e.g., C₂-C₈ alkynyl). In other embodiments, an alkynyl has two to six carbon atoms (e.g., C₂-C₆ alkynyl), In other embodiments, an alkynyl has two to four carbon atoms (e.g., C₂-C₄ alkynyl). The alkynyl is attached to the rest of the molecule by a single bond. Examples of such groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.

The term “alkoxy”, as used herein, means an alkyl group as defined herein witch is attached to the rest of the molecule via an oxygen atom. Examples of such groups include, but are not limited to, tnethoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

The term “aryl”, as used herein, refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon atoms. An amyl may comprise from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. In certain embodiments, an aryl comprises six to fourteen carbon atoms (C₆-C₁₄ aryl). In certain embodiments, an aryl comprises six to ten carbon atoms (C₆-C₁₀ aryl). Examples of such groups include, but are not limited to, phenyl, fluorenyl and naphthyl. The terms “Ph” and “phenyl,” as used herein, mean a —C₆H₅ group.

The term “heteroaryl”, refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be a monocycle, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory, fieteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of such groups include, but not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyyolyl, quinolinyl, isoquinolinyl, indolyl, benzitnidazolyl, benzofuranyl, cinnolinyl indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinvl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and the like. In certain embodiments, an heteroaryl is attached to the rest of the molecule via a ring carbon atom. In certain embodiments, an heteroaryl is attached to the rest of the molecule via a nitrogen atom (N-attached) or a carbon atom (C-attached). For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl. (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).

The term “heterocyclyl”, as used herein, means a non-aromatic, monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of from 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms in its ring system, and containing from 3 to 12 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms. A heterocyclyl group may include fused, bridged or spirocyclic ring systems. In certain embodiments, a heterocyclyl group comprises 3 to 8 ring atoms (C₃-C₈ heterocyclyl; or 3-8 membered heterocyclyl). In certain embodiments, a heterocyclyl group comprises 3 to 10 ring atoms (C₃-C₁₀ heterocyclyl; or 3-10 membered heterocyclyl). In certain embodiments, a heterocyclyl group comprises 4 to 8 ring atoms (C₄-C₈ heterocyclyl; or 4-8 membered heterocyclyl). In certain embodiments, a heterocyclyl group comprises 4 to 10 ring atoms (C₄-C₁₀ heterocyclyl; or 4-10 membered heterocyclyl). A heterocyclyl group may contain an oxo substituent at any available atom that will result in a stable compound. For example, such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible. In addition, it is to be understood that when such a heterocyclyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone. An example of a 4 membered heterocyclyl group is azetidinyl (derived from azetidine). An example of a 5 membered cycloheteroalkyl group is pyrrolidinyl. An example of a 6 membered cycloheteroalkyl group is piperidinyl. An example of a 9 membered cycloheteroalkyl group is indolinyl. An example of a 10 membered cycloheteroalkyl group is 41-1-quinolizinyl. Further examples of such heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropvranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienvl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1. 0 ]hexany 1, 3-azabicyclo[4,1.0]heptanyl, 3H-indolyl, quinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, and 1-oxo-2.8,diazaspiro[4.5]dec-8-yl. A heteroaryl group may be attached to the rest of molecular via a carbon atom (C-attached) or a nitrogen atom (N-attached). For instance, a group derived from piperazine may be piperazin-1-yl (N-attached) or piperazin-2-yl (C-attached).

The term “cycloalkyl” or “carbocyclyl” means a saturated, monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of from 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms in its ring system. A cycloalkyl may be fused, bridged or spirocyclic. In certain embodiments, a cycloalkyl comprises 3 to 6 carbon ring atoms (C₃-Co cycloalkyl; 3-6 membered cycloalkyl; or 3-6 membered carbocyclyl). In certain embodiments, a cycloalkyl comprises 3 to 8 carbon ring atoms (C₃-C₈ cycloalkyl; 3-8 membered cycloalkyl; or 3-8 membered carbocyclyl). In certain embodiments, a cycloalkyl comprises 3 to 10 carbon ring atoms (C₃-C₁₀ cycloalkyl; 3-10 membered cycloalkyl; or 3-10 membered carbocyclyl). Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

The term “cycloalkylene” is a bidentate radical obtained by removing a hydrogen atom from a cycloalkyl ring as defined above. Examples of such groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and the like.

The term “spirocyclic” as used herein has its conventional meaning, that is, any ring system containing two or more rings wherein two of the rings have one ring carbon in common. Each ring of the spirocyclic ring system, as herein defined, independently comprises 3 to 20 ring atoms. Preferably, they have 3 to 10 ring atoms. Non-limiting examples of a spirocyclic system include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

The term cyano” refers to a C≡N group.

An “aldehyde” group refers to a —C(O)H group.

An “alkoxy” group refers to both an —O-alkyl, as defined herein.

An “alkoxycarbonyl” refers to a —C(O)-alkoxy, as defined herein.

An “akiaminoalkyl” group refers to an -alkyl-NR-alkyl group, as defined herein.

An “alkylsulfonyl” group refer to a —SO₂alkyl, as defined herein.

An “amino” group refers to an optionally substituted -NH₂.

An “aminoalkyl” group refers to an -alky-amino group, as defined herein.

An “aminocarbonyl” refers to a —C(O)-amino, as defined herein.

An “arylalkyl” group refers to -alkylaryl, where alkyl and aryl are defined herein.

An “arloxy” group refers to both an —O-aryl and an —O-heteroaryl group, as defined herein.

An “aryloxycarbonyl” refers to —C(O)-aryloxy, as defined herein.

An “arylsulfonyl” group refers to a —SO₂aryl, as defined herein.

A “carbonyl” group refers to a —C(O)— group, as defined herein.

A “carboxylic acid” group refers to a —C(O)OH group.

A “cycloalkoxy” refers to a —O-cycloalkyl group, as defined herein.

A “halo” or “halogen” group refers to fluorine, chlorine, bromine or iodine.

A “haloalkyl” group refers to an alkyl group substituted with one or more halogen atoms.

A “hydroxy” group refers to an —OH group.

A “nitro” group refers to a —NO₂ group.

An “oxo” group refers to the ═O substituent.

A “trihalomethyl” group refers to a methyl substituted with three halogen atoms.

The term “substituted,” means that the specified group or moiety bears one or more substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH2, —C₁-C₈ alkyl-NH₂, —N(C 1-C₄ alkI)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo, —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH2, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C 1-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalykl).

The term “null” or “bond” means the absence of an atom or moiety, and there is a bond between adjacent atoms in the structure.

The term “optionally substituted” means that the specified group may be either unsubstituted or substituted by one or more substituents as defined herein. It is to be understood that in the compounds of the present invention when a group is said to be “unsubstituted,” or is “substituted” with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen. For example, if a C₆ aryl group, also called “phenyl” herein, is substituted with one additional substituent, one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the C₆ aryl ring (6 initial positions, minus one at which the remainder of the compound of the present invention is attached to and an additional substituent, remaining 4 positions open). In such cases, the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies. Similarly, if a C₆ aryl group in the present compounds is said to be “disubstituted,” one of ordinary skill in the art would understand it to mean that the C₆ aryl has 3 carbon atoms remaining that are tmsubstituted. Those three tmsubstituted carbon atoms are each bound to one hydrogen atom to fill their valencies.

As used herein, the same symbol in different FORMULAE refers to a different definition, for example, the definition of R1 in FORMULA 1 is as defined with respect to FORMULA 1 and the definition of RI in FORMULA 6 is as defined with respect to FORMULA 6.

As used herein, when m (or n or o or p) is defined by a range, for example, “m is 0 to 15” or “m=0-3” mean that in is an integer from 0 to 15 (i.e. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) or m is an integer from 0 to 3(i.e. m is 0, 1, 2, or 3) or is any integer in the defined range.

“Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the bivalent compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and phai maceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fwnaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997), which is hereby incorporated by reference in its entirety). Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, NN-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidineV-ethylpiperidine, polyamine resins and the like. See Berge et al,

DETAILED DESCRIPTION

The present disclosure is based in part, on the discovery that novel heterobifunctional small molecules which degrade AKT and/or AKT mutant proteins are useful in the treatment of AKT-mediated diseases, particularly developmental and over-growth syndromes, cardiovascular disease, diabetes, inflammatory and autoimmune disorders, neurological disorders, and cancer, including but not limited to colon cancer, ovarian cancer, brain cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and gastric carcinoma. Successful strategies for selective degradationidisrupfion of the target protein induced by a bifunctional small molecule include recruiting an E3 ubiquitin ligase and mimicking protein misfolding with a hydrophobic tag (Buckley and Crews, 2014). The bifunctional molecules have three moieties: one E3-binder moiety that binds an E3 ubiquitin ligase; one targeted protein-binder moiety that binds the protein target of interest; and a linker moiety that connects the E3-binder and the targeted protein-binder moieties (Buckley and Crews, 2014). The induced proximity leads to selective ubiquitination of the target followed by its degradation at the proteasome. Several types of high affinity small-molecule E3 ligase ligands have been identified/developed: immunomodulatory drugs (IMiDs) such as thalidomide and pomalidomide, which bind cereblon (CRBN or CRL4CRBN), a component of a cullin-RING ubiquitin ligase (CRL) complex (Bondeson et al., 2015; Chamberlain et al., 2014; Fischer et al., 2014; Ito et al., 2010; Winter et al., 2015); and VHL-1, a hydroxyproline-containing ligand, which binds van Hippel-Lindau protein (VHL or CRL2VHL), a component of another CRL complex (Bondeson et al., 2015; Buckley et al., 2012a; Buckley et al., 2012b; Galdeano et al., 2014; Zengerle et al., 2015). This bifunctional molecule technology has been successfully applied to degradation of multiple targets (Bondeson et al., 2015; Buckley et al., 2015; Lai et al., 2016; Lu et al., 2015; Winter et al., 2015; Zengerle et al., 2015). Recently, peptidic VHL-recruiting bifunctional molecule has been reported (Henning et al., 2016). However, there are no reported small molecule-based bifunctional molecules that lead to the degradation of AKT or AKT mutant proteins. In addition, a hydrophobic tagging approach, which utilizes a bulky and hydrophobic adamantyl group, has been developed to mimic protein misfolding, leading to the degradation of the target protein by proteasome (Buckley and Crews, 2014). This approach has been successfully applied to selective degradation of the pseudokinase Her3 (Xie et al., 2014), but not to degradation of AKT or AKT mutant proteins.

As discussed in the following examples, this disclosure provides specific examples of novel AKT degraders/disruptors, and examines the effect of exemplary degraders/disruptors on reducing AKT protein levels, inhibiting/disrupting AKT activity, and inhibiting cancer cell proliferation. The results indicate that these novel small molecules can be beneficial in treating human disease, especially developmental and over-growth syndromes, cardiovascular disease, diabetes, inflammatory and autoimmune disorders, neurological disorders, and cancer, including but not limited to colon cancer, ovarian cancer, brain cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and gastric carcinoma.

A number of selective small-molecule AKT catalytic inhibitors, such as GSK690693 (Heerding et al., 2008), GSK2110183 (Dumble et al., 2014), GSK2141795 (Dumble et al., 2014)VD5363 (Addie et aL, 2013), GDC0068 (Blake et aL, 2012), MK-2206 (Hirai et al., 2010), and ARQ-092 (Yu et al., 2015) have been in clinical trials for treating ovarian cancer, fallopian tube cancer, peritoneal cancer, neuroendocrine tumor, acute myelogenous leukemia, lymphoma, gastric and gastroesophageal junction cancer, biliary cancer, non-small cell lung cancer, pancreatic cancer, nasopharyngeal carcinoma, adenoid cystic carcinoma, endometrial cancer, colorectal cancer, breast cancer, renal cell carcinoma, prostate, glioblastoma, gliosarcoma, chronic lymphocytic leukemia, melanoma (Pretre and Wicki, 2017). Despite effectiveness in preclinical animal models, the majority of these inhibitors lack efficacy in human patients (Manning and Toker, 2017).

Currently compounds targeting AKT generally focus on inhibition of its catalytic activity. In the present disclosure, a different approach is taken: to develop compounds that directly and selectively target not only the catalytic function of AKT, but also its protein level in cells. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, mimicking protein misfolding with hydrophobic tags, and inhibiting chaperones. For example, a thalidomide-JQ1 bivalent compound has been used to hijack the cereblon E3 ligase, inducing highly selective BET protein degradation in vitro and in vivo and resulting in a demonstrated delay in leukemia progression in mice (Winter et aL, 2015). Similarly, BET protein degradation has also been induced via another E3 ligase, (Zengerle et al., 2015). Partial degradation of Her3 has been induced using an adamantane-modified compound (Xie et al., 2014). Such an approach, based on the use of bivalent small molecule compounds, permits more flexible regulation of protein levels in vitro and in vivo compared with techniques such as gene knockout or knockdown via RNA interference. Unlike gene knockout or knockdown, this chemical approach further provides an opportunity to study dose and time dependency in a disease model through varying the concentrations and frequencies of administration of the relevant compound.

This disclosure includes all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted and compounds named herein. This disclosure also includes compounds described herein, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.

This disclosure includes pharmaceutically acceptable salts of the structures depicted and compounds named herein.

One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of the hydrogen atoms in a compound can be replaced or substituted by deuterium atoms. In some embodiments, the compound includes at least one fluorine atom, In some embodiments, the compound includes two or more fluorine atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 fluorine atoms. In some embodiments, all of the hydrogen atoms in a compound can be replaced or substituted by fluorine atoms.

Degraders

In some aspects, the present disclosure provides bivalent compounds, also referred to herein as degraders, comprising an AKT ligand (or targeting moiety) conjugated to a degradation tag. Linkage of the AKT ligand to the degradation tag can be direct, or indirect via a linker.

As used herein, the terms “serine threonine kinase (AKT) ligand” or “AKT ligand” or “AKT targeting moiety” are to be construed broadly, and encompass a wide variety of molecules ranging from small molecules to large proteins that associate with or bind to AKT. The AKT ligand or targeting moiety can be, for example, a small molecule compound (i.e., a molecule of molecular weight less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, nucleic acid or oligonucleotide, carbohydrate such as oligosaccharides, or an antibody or fragment thereof.

The AKT ligand or targeting moiety can be an AKT inhibitor (e.g., GSK690693 (1-leerding et al., 2008), GSK2110183 (Dumble et al., 2014), GSK2141795 (Dumble et al. 2014), AZD5363 (Addie et al., 2013), GDC0068 (Blake et al., 2012), MK-2206 (Hirai et al., 2010), and ARQ-092 (Yu et al., 2015), and analogs thereof), which is capable of interfering with the enzymatic activity of AKT, As used herein, an “inhibitor” refers to an agent that restrains, retards, or otherwise causes inhibition of a physiological, chemical or enzymatic action or function and causes a decrease in enzyme activity of at least 5%. An inhibitor can also or alternately refer to a drug, compound, or agent that prevents or reduces the expression, transcription, or translation of a gene or protein, An inhibitor can reduce or prevent the function of a protein, e.g., by binding to or activating/inactivating another protein or receptor,

Exemplary AKT ligands include, but are not limited to, the compounds listed below:

As used herein, the term “degradation/disruption tag” refers to a compound which associates with or binds to a ubiquitin ligase for recruitment of the corresponding ubiquitination machinery to AKT or induces AKT protein misfolding and subsequent degradation at the proteasorne or loss of function.

In some aspects, the degradation/disruption tags of the present disclosure include, e.g., pomalidomide (Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide (Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al., 2017), adamantine (Xie et al., 2014), 1((4.4,5,5,5-pentalluoropentypsulfinypnonane (E. Wakeling, 1995), nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG 232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), bestatin (Hiroyuki Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161 (Weisberg et al., 2010), and/or analogs thereof.

As used herein, a “linker” is a bond, molecule, or group of molecules that binds two separate entities to one another. Linkers provide for optimal spacing of the two entities. The term “linker” in some aspects refers to any agent or molecule that bridges the AKT ligand to the degradation/disruption tag. One of ordinary skill in the art recognizes that sites on the AKT ligand or the degradation/disruption tag, which are not necessary for the function of the bifunctional molecule of the present disclosure, are ideal sites for attaching a linker, provided that the linker, once attached to the conjugate of the present disclosures, does not interfere with the function of the bifunctional molecule, i.e., its ability to target AKT, and its ability to recruit a ubiquitin ligase.

The length of the linker of the bivalent compound can be adjusted to minimize the molecular weight of the disruptors/degraders and avoid the clash of the AKT ligand or targeting moiety with the ubiquitin ligase or induce AKT misfolding by the hydrophobic tag at the same time.

In some aspects, the degradation/disruption tags of the present disclosure include, for example, pomalidomide (Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide (Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al., 2017), adamantine (Xie et al., 2014), 1-((4.4,5,5,5-pentafluoropentyl)sulfinyl)nonane (E,Wakeling, 1995), nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG 232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), bestatin (Hiroyuki Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161 (Weisberg et al., 2010), and analogs thereof. The degradation/disruption tags can be attached to each portion of interest in the structure of an AKT ligand or targeting moiety (e.g., GSK690693 (Heerding et al., 2008), GSK2110183 (Durable et al., 2014), GSK2141795 (Dumble et al., 2014), AZD5363 (Addie et al., 2013), GDC0068 (Blake et al., 2012), MK-2206 (Hirai et al., 2010), and ARQ-092 (Yu et al., 2015)) with linkers of different types and lengths in order to generate effective bivalent compounds. In particular, attaching pomalidomide or VHL-1 to either portion of the molecule can recruit the cereblon E3 ligase to AKT.

The bivalent compounds disclosed herein can selectively affect AKT-mediated disease cells compared to WT (wild type) cells (i.e., an AKT degrader,/disruptor able to kill or inhibit the growth of an AKT-mediated disease cell while also having a relatively low ability to lyse or inhibit the growth of a WI cell), e.g., possess a GI₅₀ for one or more AKT-mediated disease cells more than 1.5-fold lower, more than 2-fold lower, more than 2.5-fold lower, more than 3-fold lower, more than 4-fold lower, more than 5-fold lower, more than 6-fold lower, more than 7-fold lower, more than 8-fold lower, more than 9-fold lower, more than 10-fold lower, more than 15-fold lower, or more than 20-fold lower than its GI₅₀ for one or more WT cells, e.g., WT cells of the same species and tissue type as the AKT-mediated disease cells.

Additional bivalent compounds (i.e., AKT degraders/disruptors) can be developed using the principles and methods disclosed herein. For example, other linkers, degradation/disruption tags, and AKT binding/inhibiting moieties (not limited to GSK690693 (Heerding et al., 2008), GSK2110183 (Dumble et al., 2014), GSK2141795 (Dwnble et al., 2014), AZD5363 (Addie et al., 2013), GDC0068 (Blake et al., 2012), MK-2206 (Hirai et al., 2010), and ARQ-092 (Yu et al., 2015)) can be synthesized and tested.

In some aspects, the AKT degraders/disruptors have the form “PI-Linker-EL”, as shown below:

wherein PI (a ligand for a “protein of interest,” i.e., the protein to be degraded) comprises an AKT ligand (e.g., an AKT inhibitor), and EL (e.g., a ligand for an E3 ligase) comprises a degradation/disruption tag (e.g., E3 ligase ligand). Exemplary AKT ligands (PI), exemplary degradation/disruption tags (EL), and exemplary linkers (Linker) are illustrated below:

AKT Ligands

AKT Ligands (PI) include but are not limited to:

wherein

A, B, and X are independently N, CH, or CR⁶,

Y is CH₂, CO, SO, SO₂, CR⁷R⁸, CONR⁷, or SO₂NR⁷,

E is NH, NR⁹, O, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₇ heterocyclyl, C₂-C₈ alkenyl, C₂-C₈ alkenyl, OR⁹, SR⁹, NR⁹R¹⁰, CN, NO₂, (CR⁹R¹⁰)mNR¹¹R¹², (CR⁹R¹⁰)mC(O)R¹¹, (N R⁹R¹⁰)mNR¹¹R¹², (NR⁹R¹⁰)mC(O)R¹¹, COR⁹, CO₂R⁹, CONR⁹R¹⁰, NR⁹COR¹⁰, NR⁹SOR¹⁰, NR⁹SO₂R¹⁰, SOR⁹, SO₂R⁹, SO₂NR⁹R¹⁰, (CR⁹R¹⁰)m-acyl, or (CR⁹R¹⁰)m-heteroaryl,

R¹ is H, C₁-C₈ a C₁-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, C₁-C₈ haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,

R², R³, R⁴, and R⁶ are independently hydrogen, halogen, amino, C₁-C₈ alkylamino, arylamino, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy or C₁-C₈ alkoxyalkyl,

R⁵, R⁷, and R⁸ are independently H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, or C₁-C₈ alkoxyalkyl,

R⁹, R¹⁰, R¹¹, and R¹² are independently H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₂-C₈ alkenyl, C₂-C₈ alkynyl, arylalkyl, cycloalkyl, heterocvcloalkyl, aryl, heteroaryl, or heteroarylalkyl,

R⁹ and R¹⁰, R¹¹ and R¹² can independently form 4-8 membered alkyl or heterocyclyl rings,

m=0-8,

and

n=0-8; and

wherein

A, B and X are independently selected from N and CR⁶, wherein

R⁶ is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylamino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heteroccyclyl;

Y is selected from CR⁷R⁸, CO SO, SO₂, CONR⁷, and SO₂NR⁷, wherein

R⁷ and R⁸ is independently selected from hydrogen, halogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl; optionally substituted C₁-C₈ alkylamino, optionally substituted C₁-C₈ alkylamino C₁-C₈ alkyl, optionally substituted 3 to 10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, or

R⁷ and R⁸ together with the atom to which they are connected form an optionally substituted 3-10 membered carbocyclyl or an optionally substituted 4-10 membered heterocyclyl ring;

E is connected to the “linker” moiety of the bivalent compound, and is selected from null, R′—R″R′OR″, R′SR″, R′NR⁹R″, R′OC(O)R″, R′OC(O)OR″, R′OCONR⁹R″, R′C(O)R″, R′C(O)OR″, R′CONR⁹R″, R′S(O)R″, R′S(O)₂R″, R′SO₂NR⁹R″, R′NR¹⁰C(O)OR″, R′NR¹⁰C(O)R″, R′NR¹⁰C(O)NR⁹R″, R′NR¹⁰S(O)R″, R′NR¹⁰S(O)₂R″, and R′NR¹⁰S(O)₂NR⁹R″, wherein

R′ and R″ are independently selected from null, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-Colkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ aknylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted (C₁-C₈ alkylene)O(C₁-C₈ alkylene), optionally substituted (C₁-C₈ alkylene)N(C₁-C₈ alkylene), optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused carbocyclyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridged carbocyclyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro carbocyclyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁹ and R¹⁰ are independently selected from hydrogen, optionally substituted C₁-C₈ optionally substituted C₂-C₈ Amyl., optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkovC₁-C₈alkyl, optionally substituted C₁-C₈alky laminoC₁-C₈alky optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R⁹ and R¹⁰, R′ and R⁹, R′ and R″, R″ and R⁹, R″ and R¹⁰ together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

R¹ is selected from hydrogen, halogen, and optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted C₁-C₈ alkylamino, optionally substituted C₁-C₈ alkylamino C₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R², R³ and R⁴ are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted aryloxy, optionally substituted C₁-C₈ alkoxy,C₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylamino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted acylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

R⁵ is selected from hydrogen, optionally substituted C₁-C₈ alkyl, optionally substituted. C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyC₁-C₈ optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl; and

In one embodiment, A is selected from N, CH and CNH₂.

In another embodiment, A is N.

In one embodiment, B and X are independently selected from N and CH.

In another embodiment, B is N.

In another embodiment, X is N.

In another embodiment, Y is selected from CH, CO, CON and NHCO.

In another embodiment, Y is CO.

In another embodiment, E is selected from null, O, N, optionally substituted C₁-C₈ alkylene, optionally substituted (C₁-C₈ alkylene)O, optionally substituted (C₁-C₈ alkylene)N, optionally substituted 3-10 membered carbocyclylene, optionally substituted (3-10 membered carbocyclylene)O, optionally substituted (3-10 membered carbocyclylene)N, optionally substituted 4-10 membered heterocyclylene, optionally substituted (4-10 membered heterocyclylene)O, optionally substituted (4-10 membered heterocyclylene)N, optionally substituted aryl, and optionally substituted heteroaryl.

In another embodiment, R¹ is selected from optionally substituted aryl and optionally substituted heteroaryl.

In another embodiment, R¹ is selected from optionally substituted phenyl.

In another embodiment, R¹ is 4-chlorophenyl.

In another embodiment, R², R³, R⁴ and R⁵ are independently selected from H, F, Cl, CN, NO₂, CH₃, CF₃, iPr, and cPr.

In another embodiment, R², R⁴ and R⁵ are H.

In another embodiment, R³ is CH₃.

wherein

A, B, and X are independently N or CR³,

Y is CH₂, CO, SO, SO₂, CR⁴R⁵, CONR⁴, or SO₂NR⁴,

E is NH, NR⁶, O, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, OR⁶, SR⁶, NR⁶R⁷, CN, NO₂, (CR⁶R⁷)mNR⁸R⁹, (CR⁶R⁷)mC(O)R⁸, (N R⁶R⁷)mNR⁸R⁹, (NR⁶R⁷)mC(O)R⁸, COR⁶, CO₂R⁶, CONR⁶R⁷, NR⁶COR⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, SOR⁶, SO₂R⁶, SO₂NR⁶R⁷, (CR⁶R⁷)m-aryl, or (CR⁶R⁷)m-heteroaryl,

Z¹-Z² is CR¹⁰═CH N+CH, or CR¹⁰═N,

R¹ is hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloakl, C₁-C₈ alkoxy, C₁-C₈ al oxxa kyl, aryl, C₁-C₈ alkylaryl, haloaryl, heteroaryl, or heteroarylalkyl,

R², R³, and R⁴are independently hydrogen, halogen, amino, C₁-C₈ alkylamino, arylamino, C₁-C₈ alkyl, C₃-C₈ cycloakl, C₁-C₈ alkoxy, or C₁-C₈ alkoxyalkyl,

R⁶, R⁷, R⁸, and R⁹ are independently H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ alkoxy, C₂-C₈ alkenyl, C₂-C₈ alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl,

R⁶ and R⁷, R⁸ and R⁹ can independently form 4-8 membered alkyl or heterocyclyl rings,

R¹⁰ is hydrogen, halogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, and

n=0-8.

wherein

A, B and X are independently selected from N and CR³, wherein

R³ is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylamino C₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl ;

Z¹ is selected for CR⁸ and N, wherein

R⁸ is selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylamino C₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

Z² is selected for CH and N;

Y is selected from CO, SO, SO₂, CR⁴R⁵, CONR⁴, and SO₂NR⁴, wherein

R⁴ and R⁵ is independently selected from hydrogen and optionally substituted C₁-C₈ optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ I-C₈ alkoxy, optionally substituted C₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3 to 10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

E is connected to the “linker” moiety of the bivalent compound, and is selected from null, R′—R″, R′OR″, R′SR″, R′NR″, R″, R′OC(O)R″, R′OC(O)OR″, R′OCONR⁶R″, R′C(O)R″, R′C(O)OR″, R′CONR⁶R″, R′S(O)R″, R′S(O)₂R″, R′SO₂NR⁶R″, R′NR⁷C(O)OR″, R′NR⁷C(O)R″, R′NR⁷C(O)NR⁶R″, R′NR⁷S(O)R″, R′NR⁷S(O)₂R″, and R′NR⁷S(O)₂NR⁶R″, wherein

R′ and R″ are independently selected form null, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ alkynylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted (C₁-C₈ alkylene)O(C₁-C₈ alkylene), optionally substituted (C₁-C₈ alkylene)N(C₁-C₈ alkylene), optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused carbocyclyl, optionally substituted C₃-C fused heterocyclyl, optionally substituted C₃-C₁₃ bridged carbocyclyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro carbocyclyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁶ and R⁷ are independently selected from hydrogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkovC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alky optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R′ and R″, R⁶ and R⁷, R′ and R⁶, R′ and R⁷, R″ and R⁶, R″ and R⁷ together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

R¹ is selected from selected from hydrogen, halogen, and optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ t-C₈ alkoxyC₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkyl aminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R² is selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, or optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted amino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

In one embodiment, A is selected from N, CH and CNH₂.

In another embodiment, A is CNH₂.

In one embodiment, B and X are independently selected from N and CH.

In another embodiment, B is N.

In another embodiment, X is N.

In another embodiment, Z¹ is selected from CH and CCH3.

In another embodiment, Z¹ is CH.

In another embodiment, Z² is CH.

In another embodiment, Y is selected from CH₂, CO, CONI and NHCO.

In another embodiment, Y is CONH.

In another embodiment, E is selected from null, O, N, optionally substituted C₁-C₈ alkylene, optionally substituted (C₁-C₈ alkylene)O, optionally substituted (C₁-C₈ alkylene)N, optionally substituted 3-10 membered carbocyclylene, optionally substituted (3-10 membered carbocyclylene)O, optionally substituted (3-10 membered carbocyclylene)N, optionally substituted 4-10 membered heterocyclylene, optionally substituted (4-10 membered heterocyclylene)O, optionally substituted (4-10 membered heterocyclytene)N, optionally substituted aryl, and optionally substituted heteroaryl.

In another embodiment, R¹ is selected from optionally substituted aryl and optionally substituted heteroaryl.

In another embodiment, R¹ is selected from optionally substituted phenyl.

In another embodiment, R¹ is 4-chlorophenyl.

In another embodiment, R² is selected from H, F, Cl, CN, NO₂, CH₃, CF₃, iPr, and cPr,

In another embodiment, R² is H.

The AKT ligand can be an AKT inhibitor, such as, for example, GSK690693 (Heerding et al., 2008), GSK2110183 (Dumble et al., 2014), GSK2141795 (Dumble et al., 2014), AZD5363 (Addie et al., 2013), GDC0068 (Blake et al., 2012), MK-2206 (Hirai et al., 2010), and ARQ-092 (Yu et al., 2015), and/or analogs thereof.

In some aspects, the AIT ligand can be, e.g.:

The AKT ligand can be bound to AKT and/or AKT mutant proteins, such as, e.g., AKT with an EI7K mutation.

Degradation/Disruption Tats

Degradation/Disruption Tags (EL) include but are not limited to:

wherein

V, W, and X are independently CR² or N,

Y is CO or CH₂,

Z is CH₂, NH, or O,

R¹ is hydrogen, methyl, or fluoro, and

R² is hydrogen, halogen, or C₁-C₈ alkyl;

wherein

V, W, and X are independently selected from CR² and N;

Y is selected from CO, CH₂, and. N═N;

Z is selected from CH₂, NH and O; and

R¹ and R² are independently selected from hydrogen, halogen, cyano, nitro, and C₁-C₅ alkyl

wherein

R¹ and R² are independently hydrogen, C₁-C₈ alkyl, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ heterocyclyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl;

wherein

R¹ and R² are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ aminoalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.

R³ is selected from hydrogen, optionally substituted C(O)C₁-C₈ alkyl, optionally substituted C(O)C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted. C(O)C₁-C₈ haloalkyl, optionally substituted C(O)C₁-C₈ hydroxyalkyl, optionally substituted C(O)C₁-C₈ aminoalkyl, optionally substituted C(O)C₁-C₈alkylaminoCt-C₈alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(O)C₂-C₈ alkenyl, optionally substituted C(O)C₂-C₈ optionally substituted C(O)OC₁-C₈ alkoxyC₁-C₈alkyl, optionally substituted C(O)OC₁-C₈ haloalkyl, optionally substituted C(O)OC₁-C₈ hydroxyalkyl, optionally substituted C(O)OC₁-C₈ aminoalkyl, optionally substituted C(O)OC₁-C₈alkylaminoCt-C₈alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC₂-C₈ alkenyl, optionally substituted C(O)OC₂-C₈ alkynyl, optionally substituted C(O)NC₁-C₈ alkoxyC₁-C₈ alkyl, optionally substituted C(O)NC₁-C₈ haloalkyl, optionally substituted C(O)NC₁-C₈ hydroxyalkyl, optionally substituted C(O)NC₁-C₈ aminoalkyl, optionally substituted C(O)NC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC₂-C₈ alkenyl, optionally substituted C(O)NC₂-C₈ alkynyl, optionally substituted P(O)(OH)₂, optionally substituted P(O)(OC₁-C₈ alkyl)₂, and optionally substituted P(O)(OC₁-C₈ aryl)₂.

and

wherein

R¹, R², R³, and R⁴ are independently hydrogen, C₁-C₈ alkyl, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ heterocyclyl, C₂-C₈ alkenyl, or C₂-C₈ alkenyl, and

V, W, X, and Z are independently CR⁴ or N,

wherein

V, W, X, and Z are independently selected from CR⁴ and N; and

R¹, R², R³, and R⁴ are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈ alkynyl; optionally substituted C₁-C₈ alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkov, optionally substituted C₁-C₈alkylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.

In some aspects, the degradation/disruption tag can be, for xample, pomalidomide (Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide (Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al., 2017), adamantine (Xie et al., 2014), 1-((4.4,5,5,5-pentafluoropentypsulfinyl)nonane (E.Wakeling, 1995), nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG 232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), bestatin (Hiroyuki Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161 (Weisberg et al., 2010), and/or analogs thereof.

In some aspects, the degradation/disruption tag can be, e.g., one of the following structures:

In some aspects, the degradatiorildisruption tag can bind to a ubiquitin ligase (e.g., an E3 ligase such as a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM21 ligase, a TRIM24 ligase, and/or an TAP ligase) and/or serve as a hydrophobic group that leads to AKT protein misfolding.

Linkers

In all of the above-described compounds, the AKT ligand is conjugated to the degradation/disruption tag through a linker. The linker can include, for example, acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic and/or carbonyl containing groups with different lengths.

In some aspects, the linker can be a moiety of:

wherein

A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)NR″R¹, R′C(S)NR″R¹, R′OC(O)R″, R′OC(O)OR″, R′OCONR¹R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂NR″R¹, R′NR″R¹, R′NR¹COR″, R′NR¹C(O)OR″, R′NR¹CONR″R², R′NR¹C(S)R″, R′NR¹S(O)R″, R′NR¹S(O)₂R″, and R′NR¹S(O)₂NR²R″, wherein

R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ alkynylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted. C₁-C₈ haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C13 spiro heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl;

R¹ and R² are independently selected from hydrogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted. C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydrovalkyl, optionally substituted C₁-C₈alkylamino C₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optiondlly substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R¹ and R², R′ and R¹, R′ and R², R″ and R¹, R″ and R² together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and

m is 0 to 15.

in one embodiment, the linker moiety is of FORMULA 9A:

wherein

R¹, R², R³ and R⁴, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyakl, optionally substituted C₁-C₈ alkylamino, and optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹ and R², R³ and R⁴ together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)NR″R¹, R′C(S)NR″R¹, R′OC(O)R″, R′OC(O)OR″, R′OCONR¹R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂NR″R¹, R′NR″R¹, R′NR¹COR″, R′NR¹C(O)OR″, R′NR¹CONR″R², R′NR¹C(S)R″, R′NR¹S(O)R″, R′NR¹S(O)₂R″, and R′NR¹S(O)₂NR²R″, wherein

R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkoxyC₁-C₈alkyl, optionally substituted CA-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C,-C₈ alkynylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈ alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁵ and R⁶ are independently selected from hydrogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R⁵ and R⁶, R′ and R⁵, R′ and R⁶, R″ and R⁵, R″ and R⁶ together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

m is 0 to 15;

n, at each occurrence, is 0 to 15; and

o is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9B:

wherein

R¹ and R², at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted C₁-C₈ optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkylamino, C₁-C₈akiaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹ and R² together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)NR″R¹, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR¹R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂NR″R¹, R′NR″R¹, R′NR¹COR″, R′NR¹C(O)OR″, R′NR¹CONR″R², R′NR¹C(S)R″, R′NR¹S(O)R″, R′NR¹S(O)₂R″, and R′NR¹S(O)₂NR²R″, wherein

R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkyiaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ aikynylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈ alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C_bridged cycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R³ and R⁴ are independently selected from hydrogen, optionally substituted C₁-C₈ 1-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R³ and R⁴, R′ and R³, R′ and R⁴, R″ and R³, R″ and R⁴ together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

each m is 0 to 15; and

n is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9C:

wherein

X is selected from O, NH, and NR⁷;

R¹, R², R³, R4, R⁵, R⁶, and R⁷, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₂-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkylamino, optionally substituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered cycloalkoxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

A and B are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)NR″R¹, R′C(S)NR″R¹, R′OC(O)R″, R′OC(O)OR″, R′OCONR¹R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂NR″R¹, R′NR″R¹, R′NR¹COR″, R′NR¹C(O)OR″, R′NR¹CONR″R², R′NR¹C(S)R″, R′NR¹S(O)R″, R′NR¹S(O)₂R″, and R′NR¹S(O)₂NR²R″, wherein

R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈allyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈ alkenylene, optionally substituted C₂-C₈ alkynylene, optionally substituted C₁-C₈ hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁸ and R⁹ are independently selected from hydrogen, optionally substituted C₁-C₈ optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R⁸ and R⁹, R′ and R⁸, R′ and R⁹, R″ and R⁸, R″ and R⁹ together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

m, at each occurrence, is 0 to 15;

n, at each occurrence, is 0 to 15 ;

o is 0 to 15; and

p is 0 to 15.

In another embodiment, A and B, at each occurrence, are independently selected from null, CO, NH, NH—CO, CO—NH, CH₂—NH—CO, CH₂—CO—NH, NH—CO—CH₂, CO—NH—CH₂, CH₂—NH—CH₂—CO—NH, CH₂—NH—CH₂—NH—CO, —CO—NH, CO—NH—CH₂—NH—CH₂, CH₂—NH—CH₂.

In another embodiment, o is 0 to 5.

In another embodiment, the linker moiety comprises a ring selected from the group consisting of a 3 to 13 membered ring, a 3 to 13 membered fused ring, a 3 to 13 membered bridged ring, and a 3 to13 membered spiro ring.

In another embodiment, the linker moiety comprises one or more rings selected from the group consisting of FORMULAE C1, C₂, C₃, C₄ and C5:

wherein X is C═O or CH₂,

Y is C═O or CH₂, and

n is 0-15;

wherein X is C═O or CH₂,

Y is C═O or CH₂,

m is 0-15,

n is 0-6, and

o is 0-15; or

wherein

X is C═O or CH₂,

Y is C═O or CH₂,

R is —CH₂—, —CF₂—, —CH(C₁₋₃ alkyl)—, —C(C₁₋₃ alkyl)(C₁₋₃ alkyl)—, —CH═CH—, —C(C₁₋₃ alkyl)=C(C₁₋₃ alkyl)—, —C═C—, —O—, —NH—, —N(C₁₋₃ alkyl)-, —C(O)NH—, —C(O)N(C₁₋₃ alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring,

m is 0-15, and

n is 0-15.

In some aspects of Formula. C, R is a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring, one or more of which can contain one or more heteroatoms.

In some aspects of Formula C, R has a structure of

Synthesis and Testing of Bivalent Compounds

The binding affinity of novel synthesized bivalent compounds (i.e., AKT degraders/disruptors) can be assessed using standard biophysical assays known in the art (e.g., isothermal titration calorimetry (ITC)). Cellular assays can then be used to assess the bivalent compound's ability to induce AKT degradation and inhibit cancer cell proliferation. Besides evaluating a bivalent compound's induced changes in the protein expression of AKT or AKT mutant proteins, enzymatic activity can also be assessed. Assays suitable for use in any or all of these steps are known in the art, and include, e.g., Western blotting, quantitative mass spectrometry (MS) analysis, flow cytometry, enzymatic inhibition, ITC, SPR, cell growth inhibition and xenograft and PDX models. Suitable cell lines for use in any or all of these steps are known in the art and include, e.g., LNCaP cells (androgen-sensitive human prostate adenocarcinoma cells), PC3 (PC-3) cells (PTEN homozygous deletion mutant human prostate cancer cell lines), MCF7-neo/HER2 cells (PIK3CAE545K mutant stably expressing a HER2 transgene breast cancer cells), BT474M1. cells (PIK3CAK111N mutant and HER2-amplified human breast carcinoma), and IGROV-1 cells (PTENT319fsX1/Y155C and PIK3CA1069 Wovarian cancer cells), MDA-MB-468 cells (PTEN loss breast cancer cells), HCC₁₁₄₃ cells (Triple Negative Breast Cancer cells, TP53R248Q mutant), MDA-MB-231 (Triple Negative Breast Cancer cells), and U87MG cells (PTEN Loss Glioblastoma cells). Suitable mouse models for use in any or all of these steps are known in the art and include, e.g., PC3 prostate cancer model. MCF7-neo/HER2 breast cancer model, LNCaP prostate adenocarcinoma model, MDA-MB-468 breast cancer model, HCC₁₁₄₃ breast cancer model, and. TOV-21G.x1 ovarian cancer xenograft model.

By way of non-limiting example, detailed synthesis protocols are described in the Examples for specific exemplary AKT degraders/disruptors.

Pharmaceutically acceptable isotopic variations of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in the Examples (substituting appropriate reagents with appropriate isotopic variations of those reagents). Specifically, an isotopic variation is a compound in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature. Useful isotopes are known in the art and include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Exemplary isotopes thus include, e.g., ²H, ³H, ¹³C 14C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.

Isotopic variations (e.g., isotopic variations containing ²H) can provide therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. In addition, certain isotopic variations (particularly those containing a radioactive isotope) can be used in drug or substrate tissue distribution studies. The radioactive isotopes tritium (³H) and carbon-14 ('⁴C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Pharmaceutically acceptable solvates of the compounds disclosed herein are contemplated. A solvate can be generated, e.g., by substituting a solvent used to crystallize a compound disclosed herein with an isotopic variation (e.g., D₂O in place of H₂O, D₆-acetone in place of acetone, or d₆-DMSO in place of DMSO).

Pharmaceutically acceptable fluorinated variations of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in the Examples (substituting appropriate reagents with appropriate fluorinated variations of those reagents). Specifically, a fluorinated variation is a compound in which at least one hydrogen atom is replaced by a fluoro atom. Fluorinated variations can provide therapeutic advantages resulting from greater metabolic stability, e. increased in vivo half-life or reduced dosage requirements.

Characterization of Exemplary AKT Degraders/Disruptors

Specific exemplary AKT degraders/disruptors were characterized in various cells and mice (Examples 167-178. FIGS. 1-12 ), Bifunctional compounds XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-168, XF042-170, XF048-1, XF048-2, XF048-3, XF048-4, XF048-5, XF048-7, XF048-8, XF050-5, XF050-7, XF050-16, XF050-17, XF050-18, XF050-19, XF050-20, XF050-21, XF050-30, XF050-31, XF050-32, XF050-33, XF050-98, XF050-133, XF056-93, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, and XF056-37, in particular were found to be effective in suppressing both AKT protein level and AKT activity in BT474 cells (FIGS. 1, 3, and 4 ). We further demonstrated that XF038-166A, XF042-162, XF042-170, XF050-21, and XF050-33 induced AKT degradation is time-dependent with 24 h being the time point for the most significant AKT degradation in BT474 cells (FIGS. 2 and 5 ). Using XF050-21, we showed that the observed AKT degradation can be rescued by pretreatment of the cells with VHL-1, MLN4924, MG132 and AZD5363 (FIG. 6 ). In FIG. 7 , we compared the cell proliferation inhibition effects of AZD5363 and XF050-21. XF050-21 displayed better cell proliferation inhibition activity than AZD5363 in PC3 and MDA-MB-468 cells. In FIG. 8 , XF050-21 showed better colony formation inhibition than AZD5363 in PC3, MDA-MB-468, HCC₁₁₄₃, and MDA-MB-231 cells. In FIG. 9 , we showed that the combination treatment using an AKT degrader (XF050-21 or XF041-170) and a MTOR inhibitor (torin 1 or rapamycin) significantly reduced the AKT protein levels and AKT downstream signaling in BT474 cells. In mice, XF050-21-22 was bioavailable at 75 mg/kg via IP administration (FIG. 10 ). Additional bifunctional compounds were tested at 1 uM concentration in PC-3 cells. Compounds XF067-15, XF067-16, XF067-17, XF067-18, XF067-44, XF067-45, XF067-46, XF067-47, XF067-98, XF067-99, XF067-100, XF067-101, XF067-112 and XF067-113 were found to be effective in suppressing AKT protein level and AKT activity at 1 concentration in PC-3 cells (FIGS. 11 and 12 ).

Pharmaceutical Compositions

In some aspects, the compositions and methods described herein include the manufacture and use of pharmaceutical compositions and medicaments that include one or more bivalent compounds as disclosed herein. Also included are the pharmaceutical compositions themselves.

In some aspects, the compositions disclosed herein can include other compounds, drugs, or agents used for the treatment of cancer. For example, in some instances, phaimaceutical compositions disclosed herein can be combined with one or more (e.g., one, two, three, four, five, or less than ten) compounds. Such additional compounds can include, e.g., conventional chemotherapeutic agents known in the art. When co-administered, AKT degraders/disruptors disclosed herein can operate in conjunction with conventional chemotherapeutic agents to produce mechanistically additive or synergistic therapeutic effects.

In some aspects, the of the compositions disclosed herein can be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the AKT degraders/disruptor or its delivery form.

Pharmaceutical compositions typically include a pharmaceutically acceptable carrier, adjuvant, or vehicle. As used herein, the phrase “pharmaceutically acceptable” refers to molecular entities and compositions that are generally believed to be physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. A pharmaceutically acceptable carrier, adjuvant, or vehicle is a composition that can be administered to a patient, together with a compound of the invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Exemplary conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles include saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

In particular, pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodi um hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium thsilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyactylates, waxes, polyethylene-poly oxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, may also be advantageously used to enhance delivery of compounds of the formulae described herein. As used herein, the AKT degraders/disruptors disclosed herein are defined to include pharmaceutically acceptable derivatives or prodrugs thereof, A “pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, solvate, or prodrug, e.g., carbamate, ester, phosphate ester, salt of an ester, or other derivative of a compound or agent disclosed herein, which upon administration to a recipient is capable of providing (directly or indirectly) a compound described herein, or an active metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds disclosed herein when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. Such derivatives are recognizable to those skilled in the art without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5^(th) Edition, Vol. 1: Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.

The AKT degraders/disruptors disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, morphological forms, or deuterated derivatives thereof. In particular, pharmaceutically acceptable salts of the AKT degraders/disruptors disclosed herein include, e.g., those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsul fate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate, trifluoromethylsulfonate, and undecanoate. Salts derived from appropriate bases include, e.g., alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)4+ salts. The invention also envisions the quaternization of any basic nitrogen-containing groups of the AKT degraders/disruptors disclosed herein. Water or oil-soluble or dispersible products can be obtained by such quaternization.

In some aspects, the pharmaceutical compositions disclosed herein can include an effective amount of one or more AKT degraders/disruptors. The terms “effective amount” and “effective to treat,” as used herein, refer to an amount or a concentration of one or more compounds or a pharmaceutical composition described herein utilized for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer). In some aspects, pharmaceutical compositions can further include one or more additional compounds, drugs, or agents used for the treatment of cancer (e.g., conventional chemotherapeutic agents) in amounts effective for causing an intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer).

In some aspects, the pharmaceutical compositions disclosed herein can be formulated for sale in the United States, import into the United States, or export from the United States.

Administration of Pharmaceutical Compositions

The pharmaceutical compositions disclosed herein can be formulated or adapted for administration to a subject via any route, e.g., any route approved by the Food and Drug Administration (FDA). Exemplary methods are described in the FDA Data Standards Manual (DSM) (available at http://www,fda,gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicS ubmissions/DataStandardsManual monographs). In particular, the pharmaceutical compositions can be formulated for and administered via oral, parenteral, or transdermal delivery. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraperitoneal, intra-articular, intra-arterial, intrasynovial, intrastemal, intrathecal, intralesional, and intracranial injection or infusion techniques.

For example, the pharmaceutical compositions disclosed herein can be administered, e.g., topically, rectally, nasally (e.g., by inhalation spray or nebulizer), buccally, vaginally, subdermally (e.g., by injection or via an implanted reservoir), or ophthalmically.

For example, pharmaceutical compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule foiin, useful diluents include lactose and dried corn starch, When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emuls4ing or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

For example, the pharmaceutical compositions of this invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

For example, the pharmaceutical compositions of this invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, or other solubilizing or dispersing agents known in the art.

For example, the pharmaceutical compositions of this invention can be administered by injection (e.g., as a solution or powder). Such compositions can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, e.g., as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, e.g., olive oil or castor oil, especially in their poly oxyethyl ated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweet's, Spans, or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

In some aspects, an effective dose of a pharmaceutical composition of this invention can include, but is not limited to, e.g., about 0.00001, 0,0001, 0.001, 0.01, 0,02, 0.03, 0.04, 0.05, 0.06, 0.07, 008, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 055, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2500, 5000, or 10000 mg/kg/day, or according to the requirements of the particular pharmaceutical composition.

When the pharmaceutical compositions disclosed herein include a combination of a compound of the formulae described herein (e.g., an AKT degraders/disruptors) and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents used for the treatment of cancer or any other condition or disease, including conditions or diseases known to be associated with or caused by cancer), both the compound and the additional compound should be present at dosage levels of between about Ito 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents can be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents can be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

In some aspects, the pharmaceutical compositions disclosed herein can be included in a container, pack, or dispenser together with instructions for administration.

Methods of Treatment

The methods disclosed herein contemplate administration of an effective amount of a compound or composition to achieve the desired or stated effect. Typically, the compounds or compositions of the invention will be administered from about 1 to about 6 times per day or, alternately or in addition, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage fowl will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations can contain from about 20% to about 80% active compound.

In some aspects, the present disclosure provides methods for using a composition comprising an AKT degrader/disruptor, including pharmaceutical compositions (indicated below as ‘X’) disclosed herein in the following methods:

Substance X for use as a medicament in the treatment of one or more diseases or conditions disclosed herein (e.g., cancer, referred to in the following examples as ‘Y’). Use of substance X for the manufacture of a medicament for the treatment of Y; and substance X for use in the treatment of Y.

In some aspects, the methods disclosed include the administration of a therapeutically effective amount of one or more of the compounds or compositions described herein to a subject (e.g., a mammalian subject, e.g., a human subject) who is in need of, or who has been determined to be in need of, such treatment. In some aspects, the methods disclosed include selecting a subject and administering to the subject an effective amount of one or more of the compounds or compositions described herein, and optionally repeating administration as required for the prevention or treatment of cancer.

In sonic aspects, subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection. In some aspects, the subject can be confirmed or identified, e.g. by a health care professional, as having had or having a condition or disease. In sonic aspects, suitable subjects include, for example, subjects who have or had a condition or disease but that resolved the disease or an aspect thereof, present reduced symptoms of disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), or that survive for extended periods of time with the condition or disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), e.g., in an asymptomatic state (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease). In some aspects, exhibition of a positive immune response towards a condition or disease can be made from patient records, family history, or detecting an indication of a positive immune response. In some aspects, multiple parties can be included in subject selection. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample. In some aspects, subjects can be selected or referred by a medical practitioner (e.g., a general practitioner). In some aspects, subject selection can include obtaining a sample from a selected subject and storing the sample or using the in the methods disclosed herein. Samples can include, e.g., cells or populations of cells.

In sonic aspects, methods of treatment can include a single administration, multiple administrations, and repeating administration of one or more compounds disclosed herein as required for the prevention or treatment of the disease or condition from which the subject is suffering (e.g., an AKT-mediated disease). In some aspects, methods of treatment can include assessing a level of disease in the subject prior to treatment, during treatment, or after treatment. In some aspects, treatment can continue until a decrease in the level of disease in the subject is detected.

The term “subject,” as used herein, refers to any animal. In some instances, the subject is a mammal. in some instances, the term “subject,” as used herein, refers to a human (e.g., a man, a woman, or a child).

The terms “administer,” “administering,” or “administration,” as used herein, refer to implanting, ingesting, injecting, inhaling, or otherwise absorbing a compound or composition, regardless of form For example, the methods disclosed herein include administration of an effective amount of a compound or composition to achieve the desired or stated effect.

The terms “treat”, “treating,” or “treatment,” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating, or relieving the disease or condition from which the subject is suffering. This means any manner in which one or more of the symptoms of a disease or disorder (e.g., cancer) are ameliorated or otherwise beneficially altered. As used herein, amelioration of the symptoms of a particular disorder (e.g., cancer) refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with treatment by the compositions and methods of the present invention. In some embodiments, treatment can promote or result in, for example, a decrease in the number of tumor cells (e.g., in a subject) relative to the number of tumor cells prior to treatment; a decrease in the viability (e.g., the average/mean viability) of tumor cells (e.g., in a subject) relative to the viability of tumor cells prior to treatment; a decrease in the rate of growth of tumor cells; a decrease in the rate of local or distant tumor metastasis; or reductions in one or more symptoms associated with one or more tumors in a subject relative to the subject's symptoms prior to treatment.

As used herein, the term “treating cancer” means causing a partial or complete decrease in the rate of growth of a tumor, and/or in the size of the tumor and/or in the rate of local or distant tumor metastasis, and/or the overall tumor burden in a subject, and/or any decrease in tumor survival, in the presence of a degrader/disruptor (e.g., an AKT degrader/disruptor) described herein.

The terms “prevent,” “preventing,” and “prevention,” as used herein, shall refer to a decrease in the occurrence of a disease or decrease in the risk of acquiring a disease or its associated symptoms in a subject. The prevention may be complete, e.g., the total absence of disease or pathological cells in a subject. The prevention may also be partial, such that the occurrence of the disease or pathological cells in a subject is less than, occurs later than, or develops more slowly than that which would have occurred without the present invention. Exemplary AKT-mediated diseases that can be treated with AKT degraders/disruptors include, for example, cancer, inflammatory, hyperproliferative cardiovascular, neurodegenerative, gynecological, and dermatological diseases and disorders.

In an aspect, the AKT degraders of the present disclosure can be employed for the treatment of hyperproliferative disorders, including cancers angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, leiomyosarcoma, stomach carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenoma, villous adenoma, hamartoma, kidney cancer, Wilm's tumor, nephroblastoma, leukemia, bladder cancer, urethra cancer, transitional cell carcinoma, prostate cancer, seminoma. embryonal carcinoma, teratocarcinoma, choriocarcinoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, osteogenic sarcoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, osteoma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, endometrial carcinoma, cervical carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, intraepithelial carcinoma, melanoma, clear cell carcinoma, botryoid sarcoma, embryonal fallopian tubes carcinoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, advanced melanoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, angioma, dermatofibroma, keloids, psoriasis, neuroblastoma, metastatic breast cancer, colon cancer, oral cancer, hairy cell leukemia, head and neck cancer, refractory metastatic disease; Kaposi's sarcoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease.

The compounds and methods of this disclosure can be also used to treat diseases and conditions such as rheumatoid arthritis, osteoarthritis, Crohn's disease, angiofibroma, retinal vascularization, diabetic retinopathy, age-related macular degeneration, macular degeneration, multiple sclerosis, obesity, Alzheimer's disease, restenosis, autoimmune diseases, allergy, asthma, endometriosis, atherosclerosis, vein graft stenosis, peri-anastomatic prosthetic graft stenosis, prostate hyperplasia, chronic obstructive pulmonary disease, psoriasis, inhibition of neurological damage due to tissue repair, scar tissue formation, multiple sclerosis, inflammatory bowel disease, infections, particularly bacterial, viral, retroviral or parasitic infections, pulmonary disease, neoplasm, Parkinson's disease, transplant rejection, and septic shock,

The AKT-mediated disease can be a relapsed disease. The AKT-mediated disease can have been refractory to one or more previous treatments by different therapies.

As used herein, the term “preventing a disease” (e,g., preventing cancer) in a subject means for example, to stop the development of one or more symptoms of a disease in a subject before they occur or are detectable, e.g., by the patient or the patient's doctor. Preferably, the disease (e.g., cancer) does not develop at all, i.e., no symptoms of the disease are detectable. However, it can also result in delaying or slowing of the development of one or more symptoms of the disease. Alternatively, or in addition, it can result in the decreasing of the severity of one or more subsequently developed symptoms.

Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a therapeutic compound (i.e., an effective dosage) depends on the therapeutic compounds selected. Moreover, treatment of a subject with a therapeutically effective amount of the compounds or compositions described herein can include a single treatment or a series of treatments. For example, effective amounts can be administered at least once. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health or age of the subject, and other diseases present. Following administration, the subject can be evaluated to detect, assess, or determine their level of disease. In some instances, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected. Upon improvement of a patient's condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, or composition disclosed herein can be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced, e.g., as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

The present disclosure is also described and demonstrated by way of the following examples. However, the use of these and other examples anywhere in the specification is illustrative only and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to any particular preferred embodiment or aspect described herein. Indeed, many modifications and variations may be apparent to those skilled in the art upon reading this specification, and such variations can be made without departing from the invention in spirit or in scope. The invention is therefore to be limited only by the terms of the appended claims along with the full scope of equivalents to which those claims are entitled.

EXAMPLES Example 1 Synthesis of intermediate 2

To a solution of intermediate 1 (Blake et al., 2012) (360 mg, 0.86 mmol) in DMF (10 mL) was added potassium carbonate (358 mg, 2.6 mmol, 3 equiv). The resulting suspension was stirred at 80° C. for 15 min, before ethyl 3-bromopropanoate (310 mg, 1.72 mmol, 2 equiv) was added to the solution. After the reaction was stirred overnight, water was added to quench the reaction. The mixture was extracted with ethyl acetate (3×10 mL), dried over Na₂SO₄, filtered and evaporated. The resulting residue was purified by silica gel column (DCM/MeOH=10:1) to afford the pure product ethyl 3-(((S)-2-(4-chlorophenyl)-3-(4-45R,7R)-7-hydroxy-5-methyl-6.7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropypamino)propanoate (257 mg, yield 58%). The obtained intermediate was dissolved in THE/H₂O (1:1). To the resulting solution was added lithium hydroxide (12 mg, 0.5 mmol). After being stirred overnight at room temperature, the reaction mixture was concentrated and the residue was purified by reverse phase C18 column (10% -100% methanol/0.1% TFA in H₂O) to afford intermediate 2 as white solid in TFA salt form (238 mg, 97% yield). ¹H NMR (600 MHz, CD₃OD) δ 8.57 (d, 4.5 Hz, 1H), 7.47 (dt, J=8.7, 2.3 Hz, 2H), 7.36 (dd, J=8.4, 6.0 Hz, 2H), 5.28 (t, J=7.9 Hz 4.50 (ddd, J=9.7, 6.6, 4.1 Hz 4.37 (td, J=7.9, 4.6 Hz, 1H), 4.24-4.10 (m, 1H), 4.09-4.01 (m, 1H), 3.95-3.81 (m, 4H 3.65 (dd, f=12.9, 8.9 Hz, 3H), 3.52-3.38 (m, 2H), 3.21 (dd, J=12.8. 4.6 Hz, 1H), 2.78 (t, J=6.4 Hz, 2H), 2.28 (dd, J=12.9, 7.4 Hz, 1H), 2.17 (ddt, J=12.6, 8.3, 4.1 Hz, 1H), 1.19 (dd, J=21.1, 7.0 Hz, 3H). HRMS (m/z) for C₂₄H₃₁ClN₅O₄ ⁺ [M+H]⁺: molecular weight calculated 488.2059, found 488.2057.

Example 2 Synthesis of XF038-1.57A

To a solution of Intermediate 2 (12 mg, 0.02 mmol) in DMSO (1 mL) were added VHL-PEG1-NH₂ (11.3 mg, 0.02 mmol, 1.0 equiv), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (1-hydroxy-7-azabenzo-triazole) (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (N-Methylmorpholine) (6.1 mg, 0.06 mmol, 3.0 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF038-157A as white solid in TFA salt form (18.2 mg, 91%). ¹H NMR (600 MHz, CD₃OD) δ 8.97 (s, 1H), 8.58 (s, 1H), 7.54-7.39 (m, 6H), 7.39-7.30 (m, 2H), 5.31 (t, J=8.0 Hz, 1H), 4.71 (s, 1H), 4.61-4.45 (m, 4H), 4.42-4.36 (m, 1H), 4.17 (s, 1H), 4.08-4.03 (m, 1H), 3.99-3.76 (m, 7H), 3.71-3.54 (m, 7H), 3.47-3.36 (m, 3H), 3.28-3.23 (m, 1H), 2.80-2.64 (m, 3H), 2.48-3H), 2.22 (m, 2H), 2.17 (dt, J=12.7, 8.2 Hz, 1H), 2.09 (ddd, J=13.4, 9.4, 4.4 Hz, 1H), 1.17 (d, J=6.9 Hz, 3H), 1.04 (s, 9H). HRMS (m/z) for C₅₀H₆₆ClN₁₀O₈S⁺ [M+H]⁺: molecular weight calculated 1001.4469, found 1001.4472.

Example 3 Synthesis of VD038-158A

XF038-158A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (12 mg, 0.02 mmol), VHL-PEG2—N1-1₂ (12.3 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF038-158A was obtained as white solid in TFA salt form (9.4 mg, 45%). ¹H NMR (600 MHz, CD₃OD) δ 8.95 (s, 1H), 8.57 (s, 1H), 7.53-7.37 (m, 6H), 7.34 (dd, J=8.5, 2.1 Hz, 2H), 5.31 (t, J=7.9 Hz, 1H), 4.75 (s, 1H), 4.63-4.45 (m, 4H), 4.40 (d, J=15.5 Hz, 1H), 4.17 (s, 1H), 4.03 (d, J=2.0 Hz, 2H), 3.96-3.79 (m, 6H), 3.74-3.47 (m, 13H), 3.39 (t, J=9.5 Hz, 1H), 3.28-3.22 (m, 3H), 2.68 (t, J=6.3 Hz, 1H), 2.47 (s, 3H), 2.32-2.24 (m, 2H), 2.17 (dt, J=12.7, 8.1 Hz, 1H), 2.08 (ddd, J=13.5, 9.6, 4.3 Hz, 1H), 1.17 (dd, J=7.0, 2.0 Hz, 3H), 1.04 (s, 9H). HRMS (m/z) for C₅₂H₇₀ClN₁₀O₉S⁺ [M+H]⁺: Ur molecular weight calculated 1045.4731, found 1045.4738.

Example 4 Synthesis of XF038-159A

XF038-159A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (12 mg, 0.02 mmol), VHL-PEG4-NH₂ (14.3 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF038-159A was obtained as white solid in TFA salt form (11.2 mg, 48%). ¹H NMR (600 MHz, CD₃OD) δ 8.95 (s, 1H), 8.58 (s, 1H), 7.54-7.39 (m, 6H), 7.39-7.28 (m, 2H), 5.31 (t, J=8.01 Hz, 1H), 4.65 (s, 1H), 4.60-4.47 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 4.18 (s, 1H), 3.98-3.77 (m, 6H), 3.76-3.57 (m, 19H), 3.53 (t, J=5.4 Hz, 2H), 3.44-3.33 (m, 4H), 3.29-3.23 (m, 2H), 2.67 (t, J=6.3 Hz, 2H), 2.58 (ddd, J=15.0, 7.5, 5.2 Hz, 1H), 2.48 (s, 3H), 2.33-2.26 (m, 1H), 2.25-2.15 (m, 2H), 2.12-2.04 (m, 1H), 1.17 (d, J=6.9 Hz, 3H), 1.04 (s, 9H), HRMS (m/z) for C₅₇H₈₀ClN₁₀O₁₁S⁺ [M+H]³⁰ : molecular weight calculated 1147.5412, found 1147.5412.

Example 5 Synthesis of XF038-160A

XF038-160A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (12 mg, 0.02 mmol), VHL-C4-NH₂ (11.3 mg, 0.02 mmol, 1.0 equiv). EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM1 (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF038-160A was obtained as white solid in TFA salt form (7.6 mg, 38%). ¹H NMR (600 MHz, CD₃OD) δ 8.93 (s, 1H), 8.57 (s, 1H), 7.51-7.39 (m, 6H), 7.39-7.32 (m, 2H), 5.31 (t, J=7.91 Hz, 1H), 4.62 (s, 1H), 4.59-4.48 (m, 41I), 4.36 (d, J=15.4 Hz, 1H), 4.18 (s, 1H), 3.96-3.86 (m, 4H), 3.81 (dt, J=10.9, 6.1 Hz, 2H), 3.70-3.60 (m, 5H), 3.40 (t, J=8.9 Hz, 1H), 3.27 (dd, J=12.6, 3.8 Hz, 2H), 3.22-3.16 (m, 2H), 2.67-2.63 (m, 2H), 2.47 (s, 3H), 2.33-2.26 (m, 3H), 2.23-2.16 (m, 2H), 2.08 (ddd, J=13.3, 9.1, 4.5 Hz, 1H), 1.65-1.57 (m, 2H), 1.51 (t, J=7.4 Hz, 2H), 1.17 (c, J=7.3 Hz, 3H), 1.03 (s, 9H). HRMS (m/z) for C₅₁H₆₈ClN₁₀O₇S⁺ [M+H]⁺: molecular weight calculated 999.4676, found 999.4678.

Example 6 Synthesis of XF038-161A

XF038-161A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (12 mg, 0.02 mmol), VHL-C5-NH₂ (11.6 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF038-161A was obtained as white solid in TFA salt form (12.7 mg, 63%). ¹H NMR (600 MHz, CD₃OD) δ 8.97 (s, 1H), 8.58 (d, J=4.4 Hz, 1H), 7.54-7.38 (m, 6H), 7.38-7.32 (m, 2H), 5.31 (t, J=8.0 Hz, 1H), 4.63 (s, 1H), 4.60-4.47 (m, 4H), 4.37 (d, J=15.4 Hz, 1H), 4.18 (s, 1H), 3.97-3.78 (m, 6H), 3.72-3.54 (m, 5H), 3.40 (dd, J=10.8, 7.1 Hz, 1H), 3.29-3.24 (m, 2H), 3.18 (t, J=7.1 Hz, 2H), 2.67-2.61 (m, 2H), 2.48 (s, 3H), 2.34-2.14 (m, 5H), 2.08 (ddd, J=13.3, 9.2, 4.5 Hz, 1H), 1.66-1.57 (m, 2H), 1.50 (q, J=7.3 Hz, 2H), 1.38-1.30 (m, 2H), 1.17 (d, J=7.1 Hz, 3H), 1.03 (s, 9H). HRMS (m/z) for C₅₂H₇₀ClN₁₀O₇S⁺: [M+H]⁺: molecular weight calculated 1013.4833, found 1013.4847.

Example 7 Synthesis of XF038-162A

XF038-162A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (12 mg, 0.02 mmol), VHL-C6-NH₂ (11.9 mg 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO XF038-162A was obtained as white solid in TFA salt form (8.6 mg, 42%). ¹H NMR (600 MHz, CD₃OD) δ 8.95 (s, 1H), 8.58 (s, 1H), 7.54-7.38 (m, 6H), 7.36 (t, J=6.6 Hz, 2H), 5.38-5.26 (m, 1H), 4.64 (s, 1H), 4.61-4.48 (m, 4H), 4.37 (d, J=15.6 Hz, 1H), 4.18 (s, 1H), 3.86 (dd, J=58.9, 15.4 Hz, 6H), 3.73-3.53 (m, 5H), 3.41 (s, 1H), 3.27 (d, J=6.0 Hz, 2H), 3.23-3.10 (m, 2H), 2.72-2.57 (m, 2H), 2.48 (s, 3H), 2.33-2.17 (m, 5H), 2.10 (s, 1H), 1.66-1.58 (m, 2H), 1.53-1.46 (m, 2H), 1.39-1.31 (m, 4H), 1.17 (d, J=7.5 Hz, 3H), 1.03 (s, 9H). HRMS (m/z) for C₅₃H₇₂ClN₁₀O₇S⁺ [M+H]⁺: molecular weight calculated 1027.4989, found 1027.4983.

Example 8 Synthesis of XF038-164A

XF038-164A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (12 mg, 0.02 mmol), VHL-C8-NH₂ (12.4 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF038-164A was obtained as white solid in TFA salt form (9.9 mg, 47%). ¹H NMR (600 MHz, CD₃OD) δ 8.96 (s, 1H), 8.58 (d, J=3.7 Hz, 1H), 7.55-7.39 (m, 6H), 7.39-7.32 (m, 2H), 5.31 (t, J=8.0 Hz, 1H), 4.63 (s, 1H), 4.60-4.48 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 4.18 (s, 1H), 3.97-3.78 (m, 6H), 3.73-3.60 (m, 5H), 3.40 (t, J=8.9 Hz, 1H), 3.29-3.23 (m, 2H), 3.17 (dd, J=7.8, 6.3 Hz, 2H), 2.67-2.61 (m, 2H), 2.48 (s, 3H), 2.34-2.14 (m, 5H), 2.08 (s, 1H), 1.59 (d, J=7.0 Hz, 2H), 1.48 (d, J=7.1 Hz, 2H), 1.35-1.29 (m, 8H), 1.18 (d, J=7.0 Hz, 3H), 1.03 (s, 9H). HRMS (m/z) for C₅₅H76ClN₁₀O₇S⁺ [M+H]⁺: molecular weight calculated 1055.5302, found 1055.5303.

Example 9 Synthesis of XF038-165A

XF038-165A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (12 mg, 0.02 mmol), VHL-C9-NH₂ (12.7 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF038-165A was obtained as white solid in TFA salt form (2.8 mg, 13%). ¹H NMR (600 MHz, CD₃OD) δ 8.93 (s, 1H), 8.58 (s, 1 7.44 (d, J=25.3 Hz, 6H), 7.36 (d, J=8.5 Hz, 2H), 5.31 (d, J=8.2 Hz, 1H), 4.63 (s, 1H), 4.61-4.43 (m, 4H), 4.36 (d, J=15.3 Hz, 1H), 4.19 (s, 1H), 4.03-3.78 (m, 6H), 3.76-3.56 (m, 5H), 3.49 -3.39 (m, 1H), 3.17 (d, J=7.7 Hz, 2H), 3.03-2.95 (m, 1H), 2.91-2.83 (m, 1H), 2.65 (d, J=8.9 Hz, 2H), 2.47 (s, 3E1), 2.36-2.14 (m, 5H), 2.13-2.06 (m, 1H), 1.69-1.56 (m, 2H), 1.56-1.46 (m, 2H), 1.41-1.25 (m, 10H), 1.18 (d, J=7.0 Hz, 3H), 1.04 (s, 9H). HRMS (m/z for C₅₆H₇₈ClN₁₀O₇S⁺ [M+H]⁺: molecular weight calculated 1069.5459, found 1069.5464.

Example 10 Synthesis of XF038-166A

XF038-166A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (12 mg, 0.02 mmol), VHL-C10-NH₂ (13.0 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM) (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF038-166A was obtained as white solid in TFA salt form (11.3 mg, 52%). ¹H NMR (600 MHz, CD₃OD) δ 8.96 (s, 1H), 8.58 (d, J=3.9 Hz, 1H), 7.53-7.38 (m, 6H), 7.38-7.28 (m, 2H), 5.31 (t, 8.0 Hz, 1H), 4.63 (s, 4.60-4.44 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 4.18 (s, 1H), 3.97-3.78 (m, 6H), 3.72-3.59 (m, 5H), 3.45-3.36 (m, 1H), 3.29-3.24 (m, 2H), 3.17 (t, J=7.1 Hz, 2H), 2.67-2.62 (m, 2H), 2.48 (s, 3H), 2.34-2.16 (m, 5H), 2.12-2.04 (m, 1H), 1.60 (dt, J=15.2, 7.4 Hz, 2H), 1.49 (t, J=7.0 Hz, 2H), 1.36-1.26 (m, 12H), 1.18 (d, J=6.9 Hz, 3H), 1.03 (s, 9H). HRMS (m/z) for C₅₇H₈₀ClN₁₀O₇S⁺[M+H]⁺: molecular weight calculated 1083.5615, found 1083.5617.

Example 11 Synthesis of XF042-162

XF042-162 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.01 mg, 0.01 mmol), VHL-C10-NH₂ analog (7.4 mg, 0.01 mmol, 1.0 equiv), EDCI (2.9 mg, 0.015 mmol, 1.5 equiv), HOAt (2.1 mg, 0.015 mmol, 1.5 equiv), and NMM (3.1 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL). XF042-162 was obtained as white solid in TFA salt form (6.5 mg, 59%). ¹H NMR (600 MHz, CD₃OD) δ 8.87 (s, 1H), 8.52 (s, 1H), 7.43 (dt, J=15.8, 8.5 Hz, 6H), 7.37 (dd, J=8.6, 6.8 Hz, 2H), 5.19 (t, J=7.5 Hz, 1H), 5.00 (q, J=7.0 Hz, 1H), 4.62 (s, 1H), 4.59-4.50 (m, 2H), 4.43 (s, 1H), 4.13-4.03 (m, 1H), 4.02-3.90 (m, 1H), 3.91-3.70 (m, 7H), 3.62 (t, J=11.0 Hz, 4H), 3.59-3.51 (m, 1H), 3.43-3.37 (m, 1H), 3.26 (dd, J=12.6, 3.9 Hz, 1H), 3.17 (t, J=7.2 Hz, 2H), 2.65 (t, J=6.0 Hz, 21-1.), 2.47 (s, 3H), 2.29 (td, J=16.3, 15.4, 8.2 Hz, 1H), 2.26-2.14 (m, 3H), 195 (ddd, J=13.3, 9.1, 4.5 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H), 1.31 (s, 16H), 1.15 (d, J=7.0 Hz, 3H), 1.04 (s, 9H). HRMS (m/z) for C₅₈H₈₂ClN₁₀O₇S⁺ [M+H]⁺: molecular weight calculated 1097.5772, found 1083.5767.

Example 12 Synthesis of XF042-171

XF042-171 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.0 mg, 0.01 mmol), PML-1 (4.8 mg, 0.01 mmol, 1.0 equiv), EDCI (2.0 mg, 0.015 mmol, 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL). XF042-171 was obtained as yellow solid in TFA salt form (2.1 mg, 25%). ¹H NMR (600 MHz, CD₃OD) δ 8.56 (s, 1H), 7.57 (t, J=8.4 Hz, 1H), 7.43 (d, J=6.5 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.16-6.96 (m, 2H), 5.29 (t, J=7.8 Hz, 1H), 5.07 (d, J=12.1 Hz, 1H), 4.49 (s, 1H), 4.22-3.93 (m, 3H), 3.92-3.75 (m, 4H), 3.71 (s, 2H), 3.67-3.53 (m, 5H), 3.50 (s, 2H), 3.46-3.33 (m, 3H), 3.27-3.14 (m, 2H), 2.87 (t, J=14.8 Hz, 1H), 2.79-2.62 (m, 4H), 2.31-2.22 (m, 1H), 2.22-2.05 (m, 2H), 1.16 (d, J=6.9 Hz, 3H). HRMS (m/z) for C₄₁H₄₉ClN₉O₈ ⁺ [M+H]⁺: molecular weight calculated 830.3387, found 830.3385.

Example 13 Synthesis of XF048-7

XF048-7 was synthesized following the standard procedure for preparing XF038-1 7A from intermediate 2 (6.0 mg, 0.01 mmol), PML-2 (5.0 mg, 0.01 mmol, 1.0 equiv), EDCI (3.0 mg, 0.015 mmol, 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (I mL). XF048-7 was obtained as yellow solid in TFA salt form (5.8 mg, 64%). ¹H NMR (600 MHz, CD₃OD) δ 8.57 (s, 1H), 7.59-7.53 (m, 1H), 7.45 (dd, J=8.5, 1.8 Hz, 2H), 7.39-7.29 (m, 2H), 7.13-7.03 (m, 2H), 5.30 (t, J=7.9 Hz, 1H), 5.07 (dd, J=12.7, 5.5 Hz, 1H), 4.58-4.45 (m, 1H), 4.20-3.97 (m, 2H), 3.96-3.77 (m, 4H), 3.74-3.70 (m, 2H), 3.71-3.58 (m, 8H), 3.56 (t, J=5.5 Hz, 2H), 3.51 (t, J=5.2 Hz, 2H), 3.43-3.33 (m, 3H), 3.29-3.22 (m, 2H), 2.88 (ddd, J=17.7, 13.8, 5.3 Hz, 1H), 2.80-2.67 (m, 2H), 2.67-2.60 (m, 2H), 2.28 (dd, J=12.8, 7.5 Hz, 1H), 2.22-2.08 (m, 2H), 1.23-1.12 (m, 3H). HRMS (m/z) for C₄₃H₅₃ClN₉O₉ ⁺ [M+H]⁺: molecular weight calculated 874.3649, found 874.3650.

Example 14 Synthesis of XF048-8

XF048-8 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.1 mg, 0.01 mmol), PML-3 (5.4 mg, 0.01 mmol, 1.0 equiv), EDCI (3.0 mg, 0.015 mmol, 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL). XF048-8 was obtained as yellow solid in TFA salt form (4.7 mg, 50%). ¹H NMR (600 MHz, CD₃OD) (3 8.57 (s, 1H), 7.56 (ddd, J=8.5, 7.0, 1.3 Hz, 1H), 7.49-7.41 (m, 2H), 7.39-7.29 (m, 2H), 7.15-699 (m, 2H), 5.30 (t, J=7.9 Hz, 1H), 5.07 (dd, J=12.9, 5.4 Hz, 1H), 4.56-4.48 (m, 1H), 4.16 (s, 1H), 4.05 (s, 1H), 3.95-3.78 (m, 4H), 3.72 (t, J=5.1 Hz, 2H), 3.70-3.55 (m, 12H), 3.56-3.48 (m, 4H), 3.43-3.37 (m, 1H), 3.35 (q, J=3.9, 2.6 Hz, 2H), 3.29-3.20 (m, 2H), 2.92-2.83 (m, 1H), 2.80-2.68 (m, 2H), 168-2.61 (m, 2H), 2.29 (dd, J=12.8, 7.5 Hz, 1H), 2.21-2.09 (m, 2H), 1.17 (d, J=7.0 Hz, 3H). HRMS (m/z) for C₄₅H₅₇ClN₉O₁₀ ⁺ [M+H]⁺: molecular weight calculated 918.3911, found 918.3916.

Example 15 Synthesis of XF038-176A

XF038-176A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (9.9 mg, 0.0165 mmol), PML-4 (9.3 mg, 0.0165 mmol, 1.0 equiv), EDCI (4.8 mg, 0.025 mmol, 1.5 equiv), HOAt (3.4 ing, 0.025 mmol, 1.5 equiv), and NMM (5.1 mg, 0.05 mmol, 3.0 equiv) in DMSO (1 mL). XF038-176A was obtained as yellow solid in TFA salt form (3.5 mg, 22%). ¹H NMR (600 MHz, CD₃OD) δ 8.57 (s, 1H), 7.56 (tt, J=9.9, 7.1, 2.8 Hz, 1H), 7.49-7.41 (m, 1H), 7.37-7.24 (m, 3H), 7.10 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.1 1 Hz, 1H), 5.29 (s, 1H), 513-5.00 (m, 1H), 4.58-4.42 (m, 1H), 4.16 (s, 11-1.), 4.03 (s, 1H), 3.95-3.74 (m, 4H), 3.72 (t, J=5.2 Hz, 2H), 3.70-3.54 (m, 14H), 3.52 (dq, J=10.3, 5.4 Hz, 4H), 3.44-3.32 (m, 4H), 3.30-3.22 (m, 3H), 2.93-2.80 (m, 1H), 2.79-2.68 (m, 2H), 2.68-2.59 (m, 2H), 2.34-2.25 (m, 1H), 2.22-2.08 (m, 2H), 1.17 (d, J=7.0 Hz, 3H). HRMS (m/z) for C₄₇H₆₁ClN₉O₁₁ ⁺ [M+H]⁺: molecular weight calculated 962.4174, found 962.4167.

Example 16 Synthesis of XF038-177A

XF038-177A was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (9.9 mg, 0.0165 mmol), PML-5 (10.0 mg, 0.0165 mmol, 1.0 equiv), EDCI (4.8 mg, 0.025 mmol, 1.5 equiv), HOAt (3.4 mg, 0.025 mmol, 1.5 equiv), and NMM (5.1 mg, 0.05 mmol, 3.0 equiv) in DMSO (1 mL). XF038-177A was obtained as yellow solid in TFA salt form (5.0 mg, 30%). ¹H NMR (600 MHz, CD₃OD) δ 8.58 (d, J=3.6 Hz, 1H), 7.56 (dd, J=8.6, 7.0 Hz, 1H), 7.49-7.42 (m, 1H), 7.39-7.22 (m, 3H), 7.10 (d, J=8.5 Hz, 1H), 7.05 (d, J=7.1 Hz, 1H), 5.30 (t, J=8.0 Hz, 1H), 5.07 (ddd, J=12.9, 5.5, 2.1 Hz, 1H), 4.56-4.44 (m, 1H), 4.16 (s, 1H), 4.11-3.97 (m, 1H), 3.96-3.77 (m, 4H), 3.72 (t, J=5.2 Hz, 2H), 3.70-3.55 (m, 18H), 3.52 (dq, J=14.4, 5.3 Hz, 4H), 3.43-3.32 (m, 4H), 3.30-3.22 (m, 3H), 2.94-2.82 (m, 1H), 2.79-2.69 (m, 2H), 2.67 (dd, J=10.2, 4.0 Hz, 2H), 2.34-2.23 (m, 1H), 2.22-2.06 (m, 2H), 1.17 (d, J=7.0 Hz, 3H). HRMS (rtiz) for C₄₉H₆₅ClN₉O₁₂ ⁺ [M+H]⁺: molecular weight calculated 1006.4436, found 1006.4449.

Example 17 Synthesis of XF042-164

XF042-164 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.1 mg, 0.01 mmol), PML-13 (4.3 mg, 0.01 mmol, 1.0 equiv), EDCI (2.9 mg, 0.015 mmol, 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL). XF042-164 was obtained as yellow solid in TFA salt form (5.8 mg, 74%). ¹H NMR (600 MHz, CD₃OD) δ 8.55 (s, 1H), 7.62-7.54 1H), 7.39 (ddd, J=46.1, 8.2, 3.3 Hz, 4H), 7.13 (d, J=8.6 Hz, 1H), 7.05 (dd, J=7.0, 2.3 Hz, 1I4), 5.26 (t, J=7.7 Hz, 1H), 5.08 (dt, J=12.3, 5.9 Hz, 1H), 4.57 (d, J=9.1 Hz, 1H), 4.06 (s, 2H), 3.85 (t, J=14.7 Hz, 3H), 3.76-3.56 (m, 4H), 3.56-3.40 (m, 4H), 3.39-3.32 (m, 2H), 3.29-3.24 (m, 2H) 2.92-2.79 (m, 1H), 2.73 (t, J=18.1 Hz, 2H), 2.66 (t, J=5.6 Hz, 2H), 2.25 (t, J=10.2 Hz, 1H), 2.20-2.08 (m, 2H), 1.14 (dd, J=7.0, 1.7 Hz, 314), HRMS (m/z) for C₃₉H₄₅ClN₉O₇ ⁺ [M+H]⁺: molecular weight calculated 786.3125, found 786.3130.

Example 18 Synthesis of XF042-165

XF042-165 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.1 mg, 0.01 mmol), PML-14 (4.4 mg, 0.01 mmol, 1.0 equiv), EDCI (2.9 mg, 0.015 mmol 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL). XF042-165 was obtained as yellow solid in TFA salt form (7.8 mg, 97%). ¹H NMR (600 MHz, CD₃OD) δ 8.51 (s, 1H), 7.55 (q, J=7.0, 6.6 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.05 (td, J=8.0, 6.9, 3.6 Hz, 2H), 5.20 (t, J=7.6 Hz, 1H), 5.13-5.02 (m, 1H), 4.61-4.48 (m, 1H), 4.11-3.89 (m, 2H), 3.90-3.67 (m, 4H), 3.68-3.46 (m, 4H), 3.41 (t, J=6.5 Hz, 2H), 3.39-3.31 (m, 3H), 3.28-3.21 (m, 2H), 2.91-2.81 (m, 1H), 2.81-2.55 (m, 4H), 228-2.02 (m, 3H), 1.85 (t, J=6.6 Hz, 2H), 1.11 (d, J=7.0 Hz, 3H). HRMS (m/z) for C₄₀H₄₇ClN₉O₇ ⁺ [M+H]⁺: molecular weight calculated 800.3281, found 800.3284.

Example 19 Synthesis of XF042-166

XF042-166 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.1 mg, 0.01 mmol), PML-15 (4.6 mg, 0.01 mmol, 1.0 equiv), EDCI (2.9 mg, 0.015 mmol, 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL), XF042-166 was obtained as yellow solid in TFA salt form (5.7 mg, 70%). ¹H NMR (600 MHz, CD₃OD) δ 8.53 (s, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.35 (dd, J=8.4, 4.1 Hz, 2H), 7.05 (t, J=9.5 Hz, 2H), 5.23 (s, 1H), 5.10-5.02 (m, 1H), 4.52 (s, 1H), 4.07 (d, J=11.6 Hz, 1H), 4.03-3.89 (m, 3.89-3.71 (m, 4H), 3.71-3.50 (m, 4H), 3.42-3.33 (m, 3H), 3.26 (d, J=15.5 Hz, 4H), 2.91-2.80 (m, 1H), 2.80-2.56 (m, 4H), 2.30-2.02 (m, 3H), 1.79-1.55 (In, 4H), 1.14 (d, J=6.8 Hz, 3H). HRMS (m/z) for C₄₁H₄₉ClN₉O₇ ⁺ [M+H]⁹⁺: molecular weight calculated 814.3438, found 814.3443.

Example 20 Synthesis of XF042-167

XF042-167 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.1 mg, 0.01 mmol), PML-16 (4.7 mg, 0.01 mmol, 1.0 equiv), EDCI (2.9 mg, 0.015 mmol 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL), XF042-167 was obtained as yellow solid in TFA salt form (4.7 mg, 57%). ¹H NMR (600 MHz, CD₃OD) δ 8.54 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.35 (dd, J=8.4, 2.8 Hz, 2H), 7.04 (t, J=7.8 Hz, 2H), 5.25 (s, 1H), 5.13-5.00 (m, 1H), 4.58-4.45 (m, 1H), 4.16-3.91 (m, 2H), 3.91-3.72 (m, 4H), 3.70-3.54 (m, 4H), 3.35 (q, J=9.8, 6.8 Hz, 4H), 3.28-3.17 (m, 3H), 2.91-2.82 (m, 1H), 2.79-2.68 (m, 2H), 2.65 (d, J=6.2 Hz, 2H), 2.28-2.21 (m, 1H), 2.21-2.14 (m, 1H), 2.13-2.07 (m, 1H), 1.73-1.65 (m, 2H), 1.57 (t, J=7.5 Hz, 2H), 1.46 (d, J=7.7 Hz, 2H), 1.22-1.07 (m, 3H). HRMS (m/z) for C₄₂H₅₁ClN₉O₇ ⁺ [M+H]⁺: molecular weight calculated 828.3594, found 828.3597.

Example 21 Synthesis of XF042-168

XF042-168 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.1 mg, 0.01 nimol), PML-17 (4.9 mg, 0.01 mmol, 1.0 equiv), EDCI (2.9 mg, 0.015 mmol, 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL). XF042-168 was obtained as yellow solid in TFA salt form (4.7 mg, 57%). ¹H NMR (600 MHz, CD₃OD) δ 8.55 (s, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.39-7.27 (m, 2H), 7.04 (t, J=7.2 Hz, 2H), 5.28 (t, J=7.8 Hz, 1H), 5.05 (dd, J=12.8. 5.5 Hz, 1H), 4.56-4.48 (m, 1H), 4.14 (s, 1H), 4.09-3.97 (m, 1H), 3.92-3.73 (m, 4H), 3.70-3.56 (m, 4H), 3.42-3.32 (m, 4H), 3.28-3.23 (m, 1H), 3.19 (t, ,I=7.0 Hz, 2H), 2.90-2.81 (m, 1H), 2.77-2.68 (m, 2H), 2.68-2.60 (m, 2H), 2.27 (dd, J=12.9, 7.4 Hz, 1H), 2.21-2.13 (m, 1H), 2.13-2.06 (m, 1H), 1.68 (p, J=7.2 Hz, 2H), 1.53 (p, J=7.2 Hz, 2H), 1.49-1.43 (m, 2H), 1.40 (d, J=7.2 Hz, 2H), 1.16 (d, J=7.0 Hz, 3H), HRMS (m/z) for C₄₃H₅₃ClN₉O₇ ⁺ [M+H]⁺: molecular weight calculated 842.3751, found 842.3758.

Example 22 Synthesis of XF048-5

XF048-5 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.1 mg, 0.01 mmol), PML-18 (5.2 mg, 0.01 mmol, 1.0 equiv), EDCI (2.9 mg, 0.015 mmol 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL). XF048-5 was obtained as yellow solid in TFA salt form (8.8 mg, 98%). ¹H NMR (600 MHz, CD₃OD) δ 8.57 (d, J=4.4 Hz, 1H), 7.55 (dd, J=8.6, 7.1 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.39-7.29 (m, 2H), 7.04 (dd, J=7.8, 6.1 Hz, 2H), 5.30 (t, J=7.9 Hz, 1H), 5.05 (dd, J=12.8, 5.5 Hz, 1H), 4.52 (dt, J=9.6, 5.0 Hz, 1H), 4.16 (s, 1H), 4.04 (d, J=22.0 Hz, 1H), 3.97-3.76 (m, 4H), 3.71-3.58 (m, 4H), 3.40 (t, J=8.9 Hz, 1H), 3.34 (d, J=6.9 Hz, 2H), 3.29-3.25 (m, 2H), 3.18 (t, J=6.8 Hz, 2H), 2.86 (ddd, J=17.6, 14.0, 5.4 Hz, 1H), 2.79-2.67 (m, 2H), 2.63 (t, dr=6.3 Hz, 2H), 2.28 (dd, J=12.7, 7.5 Hz, 1H), 2.17 (dt, J=12.5, 8.1 Hz, 1H), 2.14-2.08 (m, 1H), 1.67 (p, J=7.0 Hz, 2H), 1.50 (p, J=7.2 Hz, 2H), 1.47-1.30 (m, 6H), 1.17 (d, J=6.9 Hz, 3H). HRMS (m/z) for C₄₄H₅₅ClN₉O₇ ⁺ [M+H]⁺: molecular weight calculated 856.3907, found 856.3912.

Example 23 Synthesis of XF042-170

XF042-170 was synthesized following the standard procedure for preparing XF038-157A from intermediate 2 (6.1 mg, 0.01 mmol), PML-19 (5.3 mg, 0.01 mmol, 1.0 equiv), EDCI (2.9 mg, 0.015 mmol 1.5 equiv), HOAt (2.0 mg, 0.015 mmol, 1.5 equiv), and NMM (3.0 mg, 0.03 mmol, 3.0 equiv) in DMSO (1 mL). XF042-170 was obtained as yellow solid in TFA salt form (2.8 mg, 32%). ¹f1 NMR (600 MHz, CD₃OD) δ 8.56 (s, 1H), 7.55 (dd, J=8.6, 7.0 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.41-7.29 (m, 2H), 7.04 (dd, J=7.8, 3.6 Hz, 2H), 5.28 (t, J=7.8 Hz, 1H), 5.05 (dd, J=12.8, 5.5 Hz, 1H), 4.52 (dd, J=9.3, 4.1 Hz, 1H), 4.15 (s, 1H), 4.10-3.97 (m, 1H), 3.94-3.74 (m, 4H), 3.74-3.50 (m, 4H), 3.44-3.32 (m, 4H), 3.28-3.24 (m, 1H), 3.17 (t, J=7.2 Hz, 2H), 2.86 (ddd, J=18.5, 13.8, 5.4 Hz, 1H), 2.78-2.67 (m, 2H), 2.63 (t, J=6.2 Hz, 2H), 2.27 (dd, J=12.9, 7.4 Hz, 1H), 2.21-2.14 (m, 1H), 2.14-2.06 (m, 1H), 1.67 (p, J=7.0 Hz, 2H), 1.53-1.25 (m, 10H), 1.16 (d, J=7.0 Hz, 3H). HRMS (m/z) for C₄₅H₅₇ClN₉O₇ ⁺ [M+H]⁺: molecular weight calculated 870.4064, found 870.4062.

Example 24 Synthesis of intermediate 3

To a solution of intermediate 1 (467 mg, 1.12 mmol, 1.1 equiv) in CH₃CN was added potassium carbonate (706 mg, 5 mmol, 5 equiv). After the resulting suspension was stirred at 80° C. for 15 min, benzyl (2-iodoethyl)carbamate (305 mg, 1.0 mmol) was added. The reaction was stirred at 80° C. for 8 h, before the reaction was filtered, and the filtrate was concentrated. The resulting residue was purified by preparative HPLC to afford the desired product as white solid (201 mg, yield 30%). The white solid (201 mg, 0.34 mmol) was dissolved in DCM (5 mL). To the resulting solution was added Triethylamine (92 μL, 0.68 mmol, 2 equiv) and Di-tent-butyl dicarbonate (89 mg, 0.4 mmol, 1.2 equiv). The reaction was stirred at rt for 2 h, before the solvent was removed. The resulting residue was purified by silica gel column (MeOH/DCM=1:9). The desired product was obtained (160 mg, 68% yield). After this product was dissolved in methanol (6 mL), 10% palladium on carbon was added. This reaction was stirred under H₂ for 4 h, before it was filtered. After the filtrate was concentrated, the resulting residue was purified by preparative HPLC to afford the desired product as white solid in TFA salt form (91 mg, yield 71%), ¹H NMR (600 MHz, CD₃OD) δ 8.58 (d, J=17 Hz, 1H), 7.44-7.35 (m, 2H), 7.32 (s, 2H), 5.31 (t, J=8.0 Hz, 1H), 4.32 (s, 1H), 4.21 (s, 1H), 3.98 (d, J=8.2 Hz, 1H), 3.85 (s, 2H), 3.79-3.65 (m, 6H), 3.57 (d, J=13.4 Hz, 2H), 3.51-3.41 (m, 2H), 3.03 (s, 1H), 2.29 (ddd, J=12.7, 7.3, 1.1 Hz, 1H), 2.18 (dtd, J=10.7, 7.6, 7.0, 2.91 Hz, 1H), 1.41 (s, 9H), 1.17 (d, J=7.0 Hz, 3H). HRMS (m/z) for C₂₈H₄₀ClN₆O₄ ⁺ [M+H]⁺: molecular weight calculated 559.2794, found 559.2792.

Example 25 Synthesis of XF048-1

XF048-1 was synthesized following the standard procedure for preparing XF038-157A from intermediate 3 (7.8 mg, 0.012 mmol), PML-21 (5.2 mg, 0.012 mmol, 1.0 equiv), EDCI (3.5 me, 0.018 mmol, 1.5 equiv), HOAt (2.5 mg, 0.018 mmol, 1.5 equiv), and NMM (3.6 mg, 0.036 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was obtained (8.0 mg, 68%). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 30 min, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in 1120) to afford XF048-1 as yellow solid in TFA salt form (9.6 mg, 95%). 1H NMR (600 MHz, CD₃OD) δ 8.56 (d, J=1.5 Hz, 1H), 7.56 (dd, J=8.6, 7.1 Hz, 1H), 7.49-7.39 (m, 2H), 7.34 (dd, J=8.5, 3.5 Hz, 2H), 7.08 (dd, J=19.9, 7.8 Hz, 2H), 5.30 (t, J=7.9 Hz, 1H), 5.13-5.00 (m, 1H), 4.47 (dd, J=8.8, 4.3 Hz, 1H), 4.16 (s, 1H), 3.95-3.85 (m, 2H), 3.82 (s, 2H), 3.74 (dt, J=15.1, 5.5 Hz, 4H), 3.67-3.58 (m, 8H), 3.53-3.44 (m, 4H), 3.44-3.37 (m, 1H), 3.17 (t, J=5.7 Hz, 2H), 2.91-2.82 (m, 1H), 2.78-2.63 (m, 3H), 2.48 (t, J=5.9 Hz, 2H), 2.28 (dd, J=12.9, 7.4 Hz, 1H), 2.20-2.07 (m, 2H), 1.16 (d, J=6.9 Hz, 3H). HRMS (m/z) for C₄₃H₅₃ClN₉O₉ ⁺ [M+H]⁺: molecular weight calculated 874.3649, found 874.3638.

Example 26 Synthesis of XF048-2

XF048-2 was synthesized following the standard procedure for preparing XF048-1 from intermediate 3 (7.8 mg, 0.012 mmol), PML-22 (5.7 mg, 0.012 mmol, 1.0 equiv), EDCI (3.5 mg, 0.018 mmol, 1.5 equiv), HOAt (2.5 mg, , 0.018 mmol, 1.5 equiv), and NMM (3.6 mg, 0.036 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was obtained (11.5 mg, 94%). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 30 min, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF048-2 as yellow solid in TFA salt form (8.3 mg, 82%). ¹H NMR (600 MHz, CD₃OD) δ 8.56 (s, 1H), 7.66-7.51 (m, 1H), 7.51-7.41 (m, 2H), 7.41-7.29 (m, 2H), 7.07 (dd, J=20.2, 8.0 Hz, 2H), 5.41-5.22 (m, 1H), 5.17-5.00 (m, 1H), 4.47 (dd, J=9.2, 4.7 Hz, 1H), 4.17 (s, 1H), 4.01-3.78 (m, 4H), 3.79-3.56 (m, 16H), 3.50 (p, J=8.8, 7.6 Hz, 4H), 3.41 (d, J=8.6 Hz, 2H), 3.26-3.15 (m, 2H), 2.86 (d, J=15.4 Hz, 1H), 2.82-2.63 (m, 2H), 2.55-2.43 (m, 2H), 2.28 (dd, J=12.8, 7.5 Hz, 1H), 2.24-2.05 (m, 2H), 1.16 d, J=7.1 Hz, 3H). HRMS (m/z) for C₄₅H₅₇ClN₉O₁₀ ⁺ [M+H]⁺: molecular weight calculated 918.3911, found 918.3914.

Example 27 Synthesis of XF048-3

XF048-3 was synthesized following the standard procedure for preparing XF048-1 from intermediate 3 (7.8 mg, 0.012 mmol), PML-23 (6.3 mg, 0.012 mmol, 1.0 equiv), EDCI (3.5 mg, 0.018 mmol, 1.5 equiv), HOAt (2.5 mg, 0.018 mmol, 1.5 equiv), and NMM (3.6 mg, 0.036 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was obtained (9.9 mg, 78%). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 30 min, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF048-3 as yellow solid in TFA salt form (6.9 mg, 80%). NMR (600 MHz, CD₃OD) δ 8.57 (t, J=1.6 Hz, 1H), 7.62-7.51 (m, 1H), 7.48-7.39 (m, 2H), 7.34 (ddd, J=8.5, 4.0, 1.9 Hz, 2H), 7.15-7.00 (m, 2H), 5.30 (t, J=7.9 Hz, 1H), 5.13-5.02 (m, 1H), 4.44 (d, J=8.6 Hz, 1H), 4.17 (s, 1H), 3.96-3.82 (m, 3H), 3.82-3.69 (m, 5H), 3.69-3.52 (m, 161-1), 3.52-3.44 (m, 3H), 3.42 (d, J=6.4 Hz, 1H), 3.37-3.32 (m, 1H), 3.26 (d, J=5.9 Hz, 1H), 3.21 (d, J=5.8 Hz, 2H), 2.91-2.83 (m, 1H), 2.80-2.64 (m, 2H), 2.47 (t, J=6.8 Hz, 2H), 2.29 (dd, J=12.8, 7.5 Hz, 1H), 2.21-2.07 (m, 2H), 1.16 (d, J=691 Hz, 3H). HRMS (m/z) for C₄₇H₆₁ClN₉O₁₁ ⁺ [M+H]⁺: molecular weight calculated 962.4174, found 962.4154.

Example 28 Synthesis of XF-418-4

XF048-4 was synthesized following the standard procedure for preparing XF048-1 from intermediate 3 (7.8 mg, 0.012 mmol), PML-23 (6.6 mg, 0.012 mmol, 1.0 equiv), EDCI (3.5 mg, 0.018 mmol, 1.5 equiv), HOAt (2.5 mg, 0.018 mmol, 1.5 equiv), and NMM (3.6 mg, 0.036 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was obtained (3.0 mg, 23%). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 30 min, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF048-4 as yellow solid in TFA salt form (1.2 mg, 38%). ¹H NMR (600 MHz, CD₃OD) δ 8.56 (s, 1H), 7.59-7.53 (m, 1H), 7.45 (dd, J=8.5, 2.9 Hz, 2H), 7.35 (dd, J=8.5, 3.2 Hz, 2H), 7.08 (dd, J=18.9, 7.8 Hz, 2H), 5.29 (t, J=7.9 Hz, 1H), 5.07 (dd, J=12.8, 5.5 Hz, 1H), 4.42 (dd, J=8.9, 4.3 Hz, 1H), 4.17 (s, 1H), 3.95-3.82 (m, 3H), 3.80-3.69 (m, 5H), 3.68-3.51 (m, 21H), 3.49 (t, J=5.2 Hz, 3H), 3.42 (s, 1H), 3.39-3.34 (m, 1H), 3.22 (t, J=5.6 Hz, 2H), 2.91-2.83 (m, 1H), 2.78-2.69 (m, 2H), 2.48 (t, J=5.2 Hz, 2H), 2.28 (dd, J=12.8, 7.5 Hz, 1H), 2.20-2.15 (m, 1H), 2.15-2.09 (m, 1H), 1.16 (d, J=6.9 Hz, 3H). HRMS (m/z) for C₄₉H65ClN₉O₁₁ ⁺ [M+H]⁺: molecular weight calculated 1006.4436, found 1006.4441.

Example 29 Synthesis of Intermediate 6

To a solution of Intermediate 4 (210 mg, 0.54 mmol) and Intermediate 5 (195 mg, 0.54 mmol, 1.0 equiv) (Addie et al,). in DMSO (5 mL) were added EDCI (159 mg, 0.81 mmol, 1.5 equiv), HOAt (110 mg, 0.81 mmol, 1.5 equiv), and NMM (164 mg, 1.61 mmol, 3.0 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by reverse phase column (0%-100% methanol/0.1% TFA in H₂O) to afford the desired product as white solid in TFA salt form (416 mg, 99%). After this product was dissolved in methanol (6 mL), 10% palladium on carbon was added. After this reaction was stirred under H₂ for 4 h, it was filtered through a pad of celite. The filtrate was concentrated. The resulting residue was purified by reverse phase column (0%-100% methanol/0.1% TFA in H₂O) to afford the Intermediate 6 as white solid in TFA salt form (172 mg, yield 51%). NMR (600 MHz, CD₃OD) ^(.)5 8.47-8.31 (m, 1H), 8.28 (s, 1H), 7.35 (dt, J=16.0, 5.8 Hz, 4H), 6.93 (s, 1H), 5.15-5.00 (m, 1H), 4.46-4.19 (m, 2H), 3.91-3.75 (m, 2H), 3.60-3.33 (m, 6H), 3.18-2.76 (m, 4H), 2.46-2.07 (m, 6H), 1.44 (s, 9H). HRMS (m/z) for C₃₀H₄₂ClN₈O₃ ⁺ [M+H]⁺: calculated 597.3063, found 597.3079.

Example 30 Synthesis of XF050-5

XF050-5 was synthesized following the standard procedure for preparing XF038-157A from intermediate 6 (15.9 mg, 0.022 mmol), VHL-PEG1-CH₂CO₂H (12.2 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-5 as white solid in TFA salt form (19.4 mg, 86%). ¹ H NMR (600 MHz, CD₃OD) δ 8.98 (s, 1H), 8.39 (s, 1H), 7.47-7.43 (m, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.39 (d, J=3.7 Hz, 1H), 7.37-7.31 (m, 4H), 6.94 (d, J=3.7 Hz, LH), 5.00 (dd, J=9.3, 5.8 Hz, 1H), 4.67 (s, 1H), 4.66-4.61 (m, 2H), 4.58-4.53 (m, 1H), 4.53-4.46 (m, 2H), 4.42-4.34 (m, 4H), 4.17-4.03 (m, 3H), 3.92-3.78 (m, 5H), 3.27 (dd, J=12.2, 4.4 Hz, 2H), 3.14 (td, J=12.1, 5.3 Hz, 2H), 2.72-2.58 (m, 3H), 2.47 (s, 314), 2.39-2.14 (m, 5H), 2.12-2.00 (m, 3H), 1.04 (s, 9H). HRMS (m/z) for C₅₁H₆₆ClN₁₂O₇S⁺ [M+H]⁺: calculated 1025.4581, found 1025.4590.

Example 31 Synthesis of XF050-6

XF050-6 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-PEG1-Cl₂CH₂CO₂H (12.7 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H2O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-6 as white solid in TFA salt form (11.9 mg, 52%). ¹H NMR (600 MHz, CD₃OD) δ 8.95 (s, 1H), 8.39 (s, 1H), 7.47-7.30 (m, 9H), 6.94 (d, J=3.8 Hz, 1H), 5.01 (dd, J=9.2, 5.9 Hz, 1H), 4.70-4.60 (m, 4H), 4.53 (dd, J=9.4, 7.5 Hz, 1H), 4.49-4.36 (m, 4H), 3.90-3.76 (m, 5H), 3.75-3.66 (m, 5H), 3.26 (dd, J-12.2, 4,5 Hz, 2H), 3.18-3.09 (m, 2H), 2.71-2.57 (m, 4H), 2.50 (t, J=5.9 Hz, 2H), 2.47 (s, 3H), 2.39-2.13 (m, 5H), 2.11-1.98 (m, 3H), 1.02 (s, 9H). HRMS (m/z) for C₅₃H₇₀ClN₁₂O₇S⁺ [M+H]⁺: calculated 1053.4894, found 1053.4895.

Example 32 Synthesis of XF050-7

XF050-7 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-PEG2-CH₂CO₂H (13.0 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative TAPIA: (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-7 as white solid in TFA salt form (21.1 mg, 89%). ¹H NMR (600 MHz, CD₃OD) δ 9.00 (s, 1H), 8.40 (d, J=2.8 Hz, 1H), 7.48-7.29 (m, 9H), 6.94 (d, J=3.6 Hz, 1H), 5.01 (dd, J=9.2, 5.8 Hz, 1H), 4.69 (d, J=2.7 Hz, 1H), 4.66-4.61 (m, 2H), 4.56-4.51 (m, 1H), 4.47 (d, J=17.9 Hz, 2H), 4.41-4.23 (m, 4H), 4.04 (t, J=2.9 Hz, 2H), 3.90-3.78 (m, 5H), 3.75-3.68 (m, 5H), 3.26 (dd, J=12.1, 4.3 Hz, 2H), 3.19-3.10 (m, 2H), 2.72-2.57 (m, 3H), 2.48 (s, 3H), 2.39-2.14 (m, 5H), 2.12-1.97 (m, 3H), 1.02 (s, 9H). HRMS (m/z) for C₅₃H₇₀ClN₁₂O₈S⁺ [M+H]⁺: calculated 1069.4843, found 1069.4850.

Example 33 Synthesis of XF050-8

XF050-8 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-PEG2-CH₂CH₂CO₂H (13.6 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H2O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-8 as white solid in TFA salt form (18.3 mg, 76%), ¹H NMR (600 MHz, CD₃OD) δ 9.00 (s, 1H), 8.39 (s, 1H), 7.49-7.31 (m, 9H), 6.94 (d, J=3.7 Hz, 1H), 5.02 (dd, J=9.2, 5.8 Hz, 1H), 4.64 (s, 4H), 4.59-4.45 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 3.91-3.77 (m, 5H), 3.75-3.66 (m, 5H), 3.59-3.55 (m, 4H), 3.26 (dd, J=12.3, 4.5 Hz, 2H), 3.13 (td, J=12.1, 5.2 Hz, 2H), 2.74 2.58 (m, 5H), 2.54 (dt, J=15.0, 5.9 Hz, 1H), 2.49-2.42 (m, 4H), 2.40-2.15 (m, 5H), 2.11-2.01 (m, 2H), 1.03 (s, 9H). HRMS (m/z) for C₅₅H₇₄ClN₁₂O₈S⁺ [M+H]⁺: calculated 1097.5156, found 1097.5160.

Example 34 Synthesis of X1⁷050-9

XF050-9 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-PEG3-CH₂CO₂H (14.0 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-9 as white solid in TFA salt form (19.2 mg, 78%). ¹H NMR (600 MHz, CD₃OD) δ 9.01 (d, J=3.0 Hz, 1H), 8.39 (d, J=3.0 Hz, 1H), 7.48-7.30 (m, 9H), 6.95 (d, J=3.7 Hz, 1H), 5.01 (dd, J=9.2, 5.9 Hz, 1H), 4.66 (brs, 4H), 4.57-4.48 (m, 3H), 4.37 (d, J=15.5 Hz, 1H), 4.30-4.17 (m, 2H), 4.04 (s, 2H), 3.93-3.77 (m, 5H), 3.72-3.62 (m, 9H), 3.26 (dd, J=12.2, 4.5 Hz, 2H), 3.12 (td, J=12.1, 5.2 Hz, 2H), 2.73-2.57 (m, 3H), 2.48 (d, J=2.9 Hz, 3H), 2.39-2.15 (m, 5H), 2.13-1.98 (m, 3H), 1.03 (s, 9H). HRMS (m/z) for C₅₅H₇₄ClN₁₂O₉S⁺ [M+H]⁺: calculated 1113.5105, found 1113.5120.

Example 35 Synthesis of XF050-10

XF050-10 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol). VHL-PEG3-CH₂CH₂CO₂H (14.6 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-10 as white solid in TFA salt form (13.2 mg, 53%). ¹HNMR (600 MHz, CD₃OD) δ 8.99 (s, 1H), 8.40 (s, 1H), 7.51-7.28 (m, 9H), 6.94 (d, J=3.6 Hz, 1H), 5.01 (dd, J=8.9, 6.1 Hz, 1H), 4.74-4.61 (m, 4H), 4.60-4.46 (m, 4H), 4.37 (d, J=15.5 Hz, 1H), 3.91-3.75 (m, 5H), 3.70 (dq J=16.1, 5.1, 4.1 Hz, 5H), 3.60-3.54 (m, 8H), 3.25 (dd, J=12.2, 4.5 Hz, 2H), 3.11 (td, J=12.1, 5.2 Hz, 2H), 2.73-2.52 (m, 6H), 2.48 (d, J=7.7 Hz, 4H), 2.41-2.14 (m, 5H), 2.12-2.00 (m, 2H), 1.03 (s, 9H). HRMS (m/z) for C₅₇H₇₈ClN₁₂O₉S⁺ [M+H]⁺: calculated 1141.5418, found 1141.5438.

Example 36 Synthesis of XF050-11

XF050-11 was synthesized following the standard procedure for preparing XE050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-PEG4-CH₂CH₂CO₂H (15.6 me, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-11 as white solid in TFA salt form (14.0 mg, 54%). ¹H NMR (600 MHz CD₃OD) δ 8.95 (s, 1H), 8.39 (s, 1H), 7.51-7.26 (m, 9H), 6.93 (d, J=3.7 Hz, 1H), 5.00 (dd, J=8.8, 6.3 Hz, 1H), 4.70-4.60 (m, 4H), 4.60-4.45 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 3.90-3.76 (m, 5H), 3.75-3.66 (m, 5H), 3.62-3.51 (m, 12H), 3.26 (td, J=12.4, 4.7 Hz, 2H), 3.10 (td, J=12.1, 5.3 Hz, 2H), 2.72-2.55 (m, 6H), 2.51-2.42 (m, 4H), 2.39-2.14 (m, 5H), 2.11-1.99 (m, 2H), 1.02 (s, 9H). HRMS (m/z) for C₅₉H82ClN12010S⁺ [M+H]⁺: calculated 1185.5681 found 1185.5665.

Example 37 Synthesis of XF050-12

XF050-12 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol) VHL-PEG-5-CH₂CO₂H (15.9 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-12 as white solid in TFA salt form (16.3 mg, 62%). ¹H NMR (600 MHz, CD₃OD) d 8.96 (s, 1H), 8.39 (s, 1H), 7.55-7.17 (m, 9H), 6.93 (d, J=3.7 Hz, 1H), 5.01 (t, J=7.7 Hz, 1H), 4.68-4.46 (m, 8H), 4.36 (d, J=15.5 Hz, 2H), 4.16-4.02 (m, 3H), 3.93-3.82 (m, 4H), 3.78 (dd, J=10.9, 3.8 Hz, 1H), 3.68-3.54 (m, 16H), 3.29-3.20 (m, 2H), 3.17-3.09 (m, 2H), 2.74-2.57 (m, 3H), 2.47 (s, 3H), 2.41-2.13 (m, 5H), 2.12-1.99 (m, 3H), 1.04 (s, 9H). HRMS (m/z) for C₅₉H₈₂ ClN₁₂O₁₁S⁺ [M+H]⁺: calculated 1201.5630, found 1201.5651.

Example 38 Synthesis of XF050-13

XF050-13 was synthesized following the standard procedure for preparing XE050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-PEGS-CH₂CH₂CO₂H (16.5 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 tng, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL), White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-13 as white solid in TFA salt form (17.3 mg, 64%). ¹H NMR (600 MHz, CD₃OD) d 9.00 (s, 1H), 8.40 (s, 1H), 7.53-7.28 (m, 9H), 6.94 (d, J=3.7 Hz, 1H), 5.00 (dd, J=8.9, 6.3 Hz, 1H), 4.70-4.60 (m, 4H), 4.60-4.46 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 3.91-3.76 (m, 5H), 3.76-3.67 (m, 511), 3.65-3.49 (m, 16H), 3.26 (dd, J=12.3, 4.5 Hz, 2H), 3.11 (td, J=12.2, 5.4 Hz, 2H), 2.72-2.54 (m, 6171), 2.52-2.43 (m, 4H), 2.40-2.13 (m, 5H), 2.12-1.99 (m, 2H), 1.02 (s, 9H). HRMS (m/z) for C₆₁H₈₆ClN₁₂O₁₁S⁺ [M+H]⁺: calculated 1229.5943, found 1229.5950.

Example 39 Synthesis of XF050-14

XF050-14 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-C2-CO₂H (11.7 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H2O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-14 as white solid in TFA salt form (19.9 mg, 90%). ¹H NMR (600 MHz, CD₃OD) δ 8.99 (s, 1H), 8.40 (s, 1H), 7.52-7.25 (m 9H), 6.95 (d, J=3.8 Hz, 1H), 5.01 (dd, J=9.2, 5.9 Hz, 1H), 4.71-4.60 (m, 3H), 4.60-4.45 (m, 5H), 4.37 (d, J=15.6 Hz, 1H), 3.92-3.74 (m, 5H), 3.27 (dd, J=12.3, 4.4 Hz, 2H), 3.13 (td, J=12.2, 5.2 Hz, 2H), 2.74-2.52 (m, 7H), 2.48 (s, 3H), 2.41-2.13 (m, 5H). 2.13-1.98 (m, 3H), 1.02 (s, 9H). HRMS (m/z) for C₅₁H₆₆ClN₁₂O₆S⁺ [M+H]⁺: calculated 1009.4632, found 1009.4638.

Example 40 Synthesis of XF050-15

XF050-15 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (159 mng, 0.022 mmol), VHL-C3-CO₂H (12.0 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-15 as white solid in TFA salt form (13.9 mg, 62%). ¹H NMR (600 MHz, CD₃OD) 3 9.00 (s, 1H), 8.40 (s, 1H), 7.51-7.26 (m, 9H), 6.95 (dd, J=3.7, 1.7 Hz, 1H), 5.00 (dd, J=9.2, 5.9 Hz, 1H), 4.70-4.61 (m, 3H), 4.60-4.45 (m, 5H), 4.37 (d, J=15.4 Hz, 1H), 3.94-3.75 (m, 5H), 3.26 (dd, J=12.2, 4.3 Hz, 2H), 3.12 (td, J=12.1, 5.2 Hz, 2H), 2.72-2.57 (m, 3H), 2.48 (d, J=1.5 Hz, 3H), 2.45-2.38 (m, 2H), 2.38-2.12 (m, 8H), 2.12-1.98 (m, 2H), 1.88 (p, J=7.3 Hz, 2H), 1.03 d, J=1.7 Hz, 914), HRMS (m/z) for C₅₂H₆₈ClN₁₂O₆S⁺ [M+H]⁺: calculated 1023.4789, found 1023.4794.

Example 41 Synthesis of XF050-16

XF050-16 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-C4-CO₂H (12.3 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-16 as white solid in TFA salt form (14.0 mg, 61%). ¹H NMR (600 MHz, CD₃OD) δ 9.00 (s, 1H), 8.39 (s, 1H), 7.53-7.22 (m, 9H), 6.95 (d, J=3.7 Hz, 1H), 5.00 (dd, J=9.2, 5.9 Hz, 4.69-4.59 (m, 4H), 4.59-4.44 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 3.91-3.76 (m, 5H), 3.26 (dd=12.3, 4.4 Hz, 2H), 3.13 (td, J=12.1, 5.2 Hz, 2H), 2.73-2.57 (m, 3H), 2.48 (s, 3H), 2.43 (td, J=7.1, 4.8 Hz, 2H), 2.40-2.13 (m, 8H), 2.11-2.01 (m, 2H), 1.68-1.57 (m, 4H), 1.03 (s, 9H). HRMS (m/z) for C₅₃H₇₀ClN₁₂O₆S⁺ [M+H]⁺: calculated 1037.4945, found 1017.4973,

Example 42 Synthesis of XF050-17

XF050-17 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-05-CO₂H (12.6 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O), After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-17 as white solid in TFA salt form (16.3 mg, 70%). ¹H NMR (600 MHz, CD₃OD) δ 9.04 (s, 1H), 8.40 (s, 1H), 7.55-7.25 (m, 9H), 6.95 (d, J=3.7 Hz, 1H), 5.01 (dd, J=9.3, 5.8 Hz, 1H), 4.64 (d, J=18.7 Hz, 4H), 4.58-4.45 (m, 4H), 4.37 (d, J=15.5 Hz, 1H), 3.93-3.77 (m, 5H), 3.27 (dd, J=12.3, 4.5 Hz, 2H), 3.14 (td, J=12.2, 5.2 Hz, 2H), 2.74-2.55 (m, 3H), 2.48 (s, 3H), 2.41 (t, J=7.5 Hz, 2H), 2.39-2.14 (m, 8H), 2.12-2.00 (m, 2H), 1.66-1.56 (m, 4H), 1.41-1.29 (m, 2H), 1.02 (s, 9H). HRMS (m/z) for C₅₄H₇₂ClN₁₂O₆S⁺ [M+H]⁺: calculated 1051.5102, found 1051.5094.

Example 43 Synthesis of XF050-18

XF050-18 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-C6-CO₂H (12.9 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-18 as white solid in TFA salt form (11.9 mg, 51%). ¹H NMR (600 MHz, CD₃OD) δ 8.97 (s, 1H), 8.39 (s, 1H), 7.53-7.19 (m., 9H), 6.94 (d, J=3.8 Hz, 1H), 5.01 (dd, J=9.2, 5.9 Hz, 1H), 4.71-4.61 (m, 4H), 4.59-4.45 (m, 4H), 4.36 (d, J=15.4 Hz, 1H), 3.92-3.76 (m, 5H), 3.26 (dd, J=12.3, 4.5 Hz, 2H), 3.13 (td, J=12.2, 5.3 Hz, 2H), 2.73-2.55 (m, 3H), 2.48 (s, 3H), 2.40 (t, J=7.6 Hz, 3H), 2.37-2.14 (m, 7H), 2.11-2.00 (m, 2H), 1.64-1.55 (m, 4H), 1.35 (dd, J=7.5, 4.0 Hz, 4H), 1.03 (s, 9H). HRMS (m/z) for C₅₅H₇₄ClN₁₂O₆S⁺ [M+H]⁺: calculated 1065.5258, found 1065.5272.

Example 44 Synthesis of XF050-19

XF050-19 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-C7-CO₂H (13.2 mg, 0.022 =to, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-19 as white solid in TFA salt form (10.4 mg, 44%). ¹H NMR (600 MHz, CD₃OD) δ 8.98 (s, 1H), 8.40 (d, J=1.9 Hz, 1H), 7.56 7.25 (m, 9H), 6.95 (dd, J=3.7, 1.9 Hz, 1H), 5.01 (dd, J=9.3, 5.8 Hz, 1H), 4.70-4.61 (m, 4H), 4.59-4.47 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 3.92-3.78 (m, 5H), 3.26 (dd, J=12.3, 4.3 Hz, 2H), 3.13 (td, J=12.0, 5.0 Hz, 2H), 2.73-2.58 (m, 3H), 2.48 (s, 3H), 2.43-2.37 (m, 3H), 2.37-2.14 (m, 7H), 2.11-2.00 (m, 2H), 1.65-1.54 (m, 4H), 1.34 (s, 6H), 1.03 (d, J=1.9 Hz, 9H). HRMS (m/z) for C₅₆H₇₆ClN₁₂O₆S⁺ [M+H]⁺: calculated 1079.5415, found 1079.5414.

Example 45 Synthesis of XF050-20

XF050-20 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-C8-CO₂H (13.5 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H2O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1%/TFA in H₂O) to afford XF050-20 as white solid in TFA salt form (13.6 mg, 60%). ¹H NMR (600 MHz, CD₃OD) δ 9.00 (s, 1H), 8.40 (s, 1H), 7.53-7.22 (m, 9H), 6.95 (d, J=3.8 Hz, 1H), 5.01 (dd, J=9.3, 5.8 Hz, 1H), 4.71-4.61 (m, 4H), 4.59-4.46 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 3.93-3.76 (m, 5H), 3.26 (dd, J=12.3, 4.4 Hz, 2H), 3.13 (td, J=12.2, 5.1 Hz, 2H), 2.73-2.57 (m, 3H), 2.48 (s, 3H), 2.40 (t, J=7.6 Hz, 3H), 2.37-2.14 (m, 7H), 2.11-2.00 (m, 2H), 1.63-1.53 (m, 4H), 1.32 (s, 8H), 1.03 (s, 9H). HRMS (m/z) for C₅₇H₇₈ClN₁₂O₆S⁺ [M+H]⁺: calculated 1093.5571, found 1093.5561.

Example 46 Synthesis of XF050-21

XF050-21 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), VHL-C9-CO₂H (13.8 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). White solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-21 as white solid in TFA salt form (16.0 mg, 66%). ¹H NMR (600 MHz, CD₃OD) δ 8.97 (s, 1H), 8.39 (s, 1H), 7.53-7.25 (m, 9H), 6.94 (d, J=3.8 Hz, 1H), 5.01 (dd, J=9.4, 5.8 Hz, 1H), 4.69-4.59 (m, 4H), 4.59-4.47 (m, 4H), 4.36 (d, J=15.5 Hz, 1H), 3.93-3.78 (m, 5H), 3.26 (dd, J=12.3, 4.5 Hz, 2H), 3.14 (td, J=12.2, 5.1 Hz, 2H), 2.74-2.57 (m, 3H), 2.48 (s, 3H), 2.40 (t, J=7.6 Hz, 3H), 2.37-2.15 (m, 7H), 2.11-2.00 (m, 2H), 1.58 (td, J=10.8, 8.0, 4.1 Hz, 4H), 1.31 (s, 10H), 1.03 (s, 9H). HRMS (m/z) for C₅₈H80ClN₁₂O₆S⁺ [M+H] calculated 1107.5928, found 1107.5926.

Example 47 Synthesis of XF050-22

XF050-22 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-6 (7.3 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-22 as yellow solid in TFA salt form (2.9 mg, 16%). ¹H NMR (600 MHz, CD₃OD) δ 8.36 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.44 (dd, J=8.5, 7.0 Hz, 1H), 7.36 (dd, J=12.3, 2.7 Hz, 3H), 7.10 (d, J=7.2 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 6.99 (dd, J=8.4, 3.6 Hz, 1H), 6.89 (d, J=3.7 Hz, 1H), 5.10-4.99 (m, 2H), 4.75-4.64 (m, 2H), 4.24 (s, 2H), 3.76 (q, J=12.1 Hz, 4H), 3.44-3.32 (m, 2H), 3.28-3.22 (m, 2H), 3.12 (td, J=12.2-5.2 Hz, 2H), 2.90-2.80 (m, 2H), 2.78-2.51 (m, 5H), 2.40-2.24 (m, 2H), 2.17-2.06 (m, 2H), 2.04-1.96 (m, 1H). HRMS (m/z) for C₄₀H₄₅ClN₁₁O₆ ⁺ [M+H]⁺: calculated 810.3237, found 810.3246.

Example 48 Synthesis of XF050-23

XF050-23 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-7 (7.6 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-23 as yellow solid in TFA salt form (16.2 mg, 89%). ¹H NMR (600 MHz, CD₃OD) δ 8.38 (s, 1H), 7.56 (dd, J=8.5, 7.2 Hz, 1H), 7.39-7.31 (m, 5H), 7.11 (d, J=8.6 Hz, 1H), 7.05 (d, J=7.1 Hz, 1H), 6.93 (d, J=3.7 Hz, 1H), 5.07-4.97 (m, 2H), 4.64 (s, 2H), 3.84 (q, J=12.2 Hz, 4H), 3.68-3.63 (m, 4H), 3.26-3.15 (m, 2H), 3.08 (td, J=11.9, 4.9 Hz, 2H), 2.90-2.79 (m, 2H), 2.77-2.71 (m, 3H), 2.71-2.58 (m, 3H), 2.37-1.98 (m, 6H). HRMS (m/z) for C₄₁H₄₇ClN₁₁O₆ ⁺ [M+H]⁺: calculated 824.3394, found 824.3394.

Example 49 Synthesis of XF050-24

XF050-24 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-8 (7.9 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-24 as yellow solid in TFA salt form (12.5 mg, 68%). ¹H NMR (600 MHz, CD₃OD) δ 8.39 (s, 1H), 7.54 (dd, J=8.5, 7.2 Hz, 1H), 7.37 (dd, J=17.5, 3.5 Hz, 5H), 7.10 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.1 Hz, 1H), 6.94 (d, J=3.7 Hz, 1H), 5.05 (dd, J=12.8, 5.5 Hz, 1H), 5.00 (dd, J=9.2, 5.9 Hz, 1H), 4.70-4.60 (m, 2H), 3.84 (dd, J=13.8, 10.5 Hz, 4H), 3.39 (t, J=6.7 Hz, 4H), 3.23 (t, J=12.2 Hz, 2H), 3.08 (ddd, J=17.1, 11.5, 4.9 1 Hz, 2H), 2.93-2.79 (m, 2H), 2.78-2.57 (m, 5H), 2.53 (t, J=6.9 Hz, 2H), 2.34 (d, J=11.8 Hz, 1H), 2.26 (dd, J=12.3, 6.2 Hz, 1H), 2.17 (d, J=14.9 Hz, 1H), 2.10 (ddd, J=10.5, 5.5, 3.0 Hz, 1H), 2.04 (d, J=14.7 Hz, 1H), 1.99-1.94 (m, 2H). HRMS (m/z) for C₄₂H₄₉ClN₁₁O₆ ⁺ [M+H]⁺: calculated 838.3550, found 838.3552.

Example 50 Synthesis of XF050-25

XF050-25 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-9 (8.2 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H20). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-25 as yellow solid in TFA salt form (9.6 mg, 51%). ¹H NMR (600 MHz, CD₃OD) δ 8.38 (5, 1H), 7.54 (dd, J=8.4, 7.2 Hz, 1H), 7.36 (dd, J=6.5, 3.5 Hz, 5H), 7.07-7.00 (m, 2H), 6.91 (d, J=3.7 Hz, 1H), 5.05 (ddd, J=12.8, 5.5, 2.0 Hz, 1H), 5.00 (dd, J=9.2, 5.9 Hz, 1H), 4.71-4.61 (m, 2H), 3.82 (q, J=12.0 Hz, 4H), 3.36 (d, J=5.8 Hz, 4H), 3.24 (td, J=12.3, 4.5 Hz, 2H), 3.10 (td, J=11.9, 4.9 Hz, 2H), 2.85 (dddd, J=19.5, 14.1,5.3. 2.2 Hz, 2H), 2.78-2.55 (m, 5H), 2.48 (s, 2H), 2.38-2.29 (m, 1H), 2.25 (tt, J=12.2, 5.5 Hz, 1H), 2.19-2.06 (m, 2H), 2.02 (d, J=14.6 Hz, 1H), 1.75-1.67 (m, 4H). HRMS (m/z) for C₄₃H51ClN₁₁O₆ ⁺ [M+H]⁺: calculated 8520.3707, found 852.3710.

Example 51 Synthesis of XF050-26

XF050-26 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-10 (8.5 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H2O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-26 as yellow solid in TFA salt form (13.9 mg, 73%). ¹H NMR (600 MHz, CD₃OD) δ 8.39 (s, 1H), 7.59-7.48 (m, 1H), 7.43-7.24 (m, 5H), 7.03 (dd, J=7.8, 5.8 Hz, 2H), 6.93 (d, J=3.7 Hz, 1H), 5.09-4.96 (m, 2H), 4.70-4.57 (m, 2H), 3.85 (q, J=12.1 Hz, 4H), 3.33 (t, J=6.8 Hz, 4H), 3.29-3.22 (m, 2H), 3.11 (td, J=12.2, 5.1 Hz, 2H), 2.92-2.79 (m, 2H), 2.78-2.57 (m, 5H), 2.43 (t, J=7.4 Hz, 2H), 2.38-2.30 (m, 1H), 2.26 (tt, J=12.1, 5.5 Hz, 1H), 2.17 (d, J=14.7 Hz, 1H), 2.13-2.07 (m, 1H), 2.07-1.99 (m, 1H), 1.73-1.61 (m, 4H), 1.46 (tt, J=9.9, 6.4 Hz, 2H). HRMS (m/z) for C₄₄H₅₃ClN₁₁O₆ ⁺ [M+H]⁺: calculated 866.3863, found 866.3859.

Example 52 Synthesis of XF050-27

XF050-27 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-11 (8.8 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-27 as yellow solid in TFA salt foun (14.5 mg, 75%). ¹H NMR (600 MHz, CD₃OD) δ 8.39 (s, 1H), 7.54 (dd, J=8.6, 7.1 Hz, 1H), 7.40-7.30 (m, 5H), 7.03 (t, J=7.3 Hz, 2H), 6.94 (d, J=3.7 Hz, 1H), 5.08-4.96 (m 2H), 4.65 (d, J=13.8 Hz, 2H), 3.85 (q, J=12.1 Hz, 4H), 3.36-3.30 (m, 4H), 3.27 (td, J=12.4, 4.5 Hz, 2H), 3.12 (td, J=12.1, 5.1 Hz, 2H), 2.91-2.78 (m, 2H), 2.77-2.59 (m, 5H), 2.41 (d, J=1.6 Hz, 2H), 2.37-2.31 (m, 1H), 2.26 (d, 1H), 2.17 (d, J=15.0 Hz, 1H), 2.14-2.07 (m, 1H), 2.07-1.98 (m, 1H), 1.64 (dp, J=37.0, 7.2 Hz, 4H), 1.49-1.35 (m, 4H). HRMS (m z) for C₄₅H₅₅ClN₁₁O₆ ⁺ [M+H]⁺: calculated 880.4020, found 880.4026.

Example 53 Synthesis of XF050-28

XF050-28 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-12 (9.1 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H2O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-28 as yellow solid in TFA salt form (15.5 mg, 78%). ¹H NMR (600 MHz, CD₃OD) δ 8.39 (s, 1H), 7.54 (dd, J=8.6, 7.1 Hz, 1H), 7.39-7.32 (m, 5H), 7.03 (dd, J=7.8, 4.3 Hz, 2H), 6.94 (d, J=3.7 Hz, 1H), 5.08-4.97 (m, 2H), 4.68-4.62 (m, 2H), 3.84 (q, J=12.2 Hz, 4H), 3.35-3.31 (m, 4H), 3.28-3.24 (m, 2H), 3.12 (td, J=12.2, 5.2 Hz, 2H), 2.85 (ddd, J=17.6, 13.9, 5.4 Hz, 2H), 2.78-2.56 (m, 5H), 2.39 (t, J=7.5 Hz, 2H), 2.34 (t, J=10.4 Hz, 1H), 2.26 (tt, J=12.1, 5.5 Hz, 1H), 2.17 (d, J=14.8 Hz, 1H), 2.10 (ddt, J=13.1, 5.6, 2.8 Hz, 1H), 2.03 (d, J=14.6 Hz, 1H), 1.66 (p, J=7.1 Hz, 2H), 1.58 (p, J=7.5 Hz, 2H), 1.47-1.33 (m, 6H). HRMS (m/z) for C₄₆H57ClN₁₁O₆ ⁺ [M+H]⁺: calculated 894.4176, found 894.4192.

Example 54 Synthesis of XF050-29

XF050-29 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-20 (8.6 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-29 as yellow solid in TFA salt form (16.7 mg, 87%). ¹H NMR (600 MHz, CD₃OD) δ 8.39 (s, 1H), 7.57 (ddd, J=8.6, 7.1, 3.9 Hz, 1H), 7.37 (dd, J=3.9, 1.1 Hz, 1H), 7.34-7.28 (m, 4H), 7.10-7.03 (m, 2H), 6.93 (dd, J=3.7, 1.5 Hz, 1H), 5.04 (ddd, J=12.7, 5.5, 2.3 Hz, 1H), 4.68-4.59 (m, 3H), 3.91-3.74 (m, 6H), 3.70 (tt, J=4.7, 2.2 Hz, 3H), 3.48 (td, J=4.9, 4.3, 2.3 Hz, 3H), 3.15 (td, J=15.0, 13.5, 8.3 Hz, 2H), 2.95 (dq, J=12.2, 5.7 Hz, 2H), 2.88-2.78 (m, 2H), 2.77-2.54 (m, 6H), 2.32-2.06 (m, 5H), 2.02 (d, J=14.6 Hz, 1H). HRMS (m/z) for C₄₃H₅₁ClN₁₁O₇ ⁺ [M+H]⁺: calculated 868.3656, found 868.3661.

Example 55 Synthesis of XF050-30

XF050-30 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-21 (9.5 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol 0.1% TFA in H₂O) to afford XF050-30 as yellow solid in TFA salt foun (15.8 mg, 79%). ¹H NMR (600 MHz, CD₃OD) δ 8.38 (s, 1H), 7.54 (ddt, J=8.6, 7.1, 1.4 Hz, 1H), 7.37 (dd, J=3.8, 1.3 Hz, 1H), 7.34-7.28 (m, 4H), 7.08 (d, J=8.5 Hz, 1H), 7.04 (dd, J=7.0, 2.7 Hz, 1H), 6.92 (dd, J=3.8, 1.6 Hz, 1H), 5.05 (ddd, J=12.6, 5.4, 3.8 Hz, 1H) 4.96 (dt, J=9.6, 3.9 Hz, 1H), 4.68-4.54 (m, 3H). 3.89-3.80 (m, 3H), 3.73 (td, J=6.0, 1.7 Hz, 2H), 3.68 (td, J=5.2, 2.3 Hz, 2H), 3.65-3.54 (m, 5H), 3.46 (t, J=5.1 Hz, 3H), 3.22 (td, J=12.3, 4.41 Hz, 2H), 3.10-3.01 (m, 2H), 2.84 (ddt, J=17.7, 13.8, 4.6 Hz, 2H), 2.77-2.57 (m, 6H), 2.35-2.07 (m, 5H), 2.02 (d, J=14.7 Hz, 1H). HRMS (m/z) for C₄₅H₅₅ClN₁₁O₈ ⁺ [M+H]⁺: calculated 912.3918, found 912.3902.

Example 56 Synthesis of XF050-31

XF050-31 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-22 (10.5 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), MAI (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H2O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-31 as yellow solid in TFA salt form (16.2 mg, 77%). ¹H NMR (600 MHz, CD₃OD) δ 8.38 (s, 1H), 7.54 (ddd, J=8.6, 7.1, 1.5 Hz, 1H), 7.39-7.28 (m, 5H), 7.07 (d, J=8.6 Hz, 1H), 7.04 (s, 1H), 6.92 (dd, J=3.7, 1.6 Hz, 1H), 5.05 (ddd, J=12.6, 5.4, 1.5 Hz, 1H), 4.99 (ddd, J=9.4, 6.2, 3.8 Hz, 1H), 4.67-4.53 (m, 3H), 3.91-3.80 (m, 3H), 3.73-3.67 (m, 4H), 3.64-3.53 (m, 8H), 3.53-3.44 (m, 4H), 3.25 (t, J=12.8 Hz, 2H), 3.09 (td, J=11.9, 5.7 Hz, 2H), 2.91-2.80 (m, 2H), 2.77-2.57 (m, 7H), 2.37-2.23 (m, 2H), 2.20-2.07 (m, 2H), 2.03 (d, J=14.7 Hz, 1H), HRMS (m/z) for C₄₇H₅₉ClN₁₁O₉ ⁺ [M+H]⁺: calculated 956.4180, found 956.4183.

Example 57 Synthesis of XF050-32

XF050-32 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-23 (11.5 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg, 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-32 as yellow solid in TFA salt form (12.8 mg, 58%). ¹H NMR (600 MHz, CD₃OD) δ 8.38 (s, LH), 7.54 (ddd, J=8.6, 7.1, 1.5 Hz, 1H), 7.38-7.31 (m, 5H), 7.08 (d, J=8.5 Hz, 1H), 7.04 (dd, J=7.1, 2.1 Hz, 1H), 6.92 (dd, J=3.8, 1.3 Hz, 1H), 5.05 (dd, J=12.8, 5.5 Hz, 1H), 5.02-4.96 (m, 1H), 4.68-4.57 (m, 3H), 3.85 (dt, J=15.4, 9.3 Hz, 3H), 3.73-3.68 (m, 4H), 3.62 (m, J=5.6, 3.6, 1.9 Hz, 4H), 3.59-3.53 (m, 9H), 3.49 (t, J=5.2 Hz, 3H), 3.25 (td, J=12.1, 4.3 Hz, 2H), 3.09 (td, J=12.1, 5.4 Hz, 2H), 2.89-2.80 (m, 2H), 2.77-2.56 (m, 7H), 2.38-2.24 (m, 2H), 2.19-2.08 (m, 2H), 2.03 (d, J=14.7 Hz, 1H). HRMS (m/z) for C₄₉H₆₃ClN₁₁O₁₀ ⁺ [M+H]⁺: calculated 1000.4442, found 1000.4462.

Example 58 Synthesis of XF050-33

XF050-33 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (15.9 mg, 0.022 mmol), PML-24 (12.5 mg, 0.022 mmol, 1.0 equiv), EDCI (6.5 mg. 0.033 mmol, 1.5 equiv), HOAt (4.5 mg, 0.033 mmol, 1.5 equiv), and NMM (6.7 mg, 0.066 mmol, 3.0 equiv) in DMSO (1 mL). Yellow solid in TFA salt form was isolated by preparative HPLC (10%-100% methanol/0.1% TFA in H2O). After this solid was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction was stirred at rt for 2 h, before the solvent was evaporated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-33 as yellow solid in TFA salt form (5.0 mg, 22%). ¹H NMR (600 MHz, CD₃OD) 8.37 (s, 1H), 7.55 (ddd, J=8.4, 7.2, 0.9 Hz, 1H), 7.38-7.31 (m, 5H), 7.08 (d, J=8.6 Hz, 1H), 7.05 (dd, J=7.1, 1.3 Hz, 1H), 6.89 (d, J=3.7 Hz, 1H), 5.05 (dd, J=12.8, 5.5 Hz, 1H), 5.02-4.97 (m, 1H), 4.71-4.59 (m, 3H), 3.84-3.75 (m, 3H), 3.71 (t, J=5.3 Hz, 4H), 3.66-3.58 (m, 7H), 3.58-3.51 (m, 10H), 3.49 (t, J=5.2 Hz, 3H), 3.24 (td, J=12.0, 4.2 Hz, 2H), 3.08 (td, J=12.1, 5.4 Hz, 2H), 2.90-2.80 (m, 2H), 2.78-2.55 (m, 7H), 2.37-2.22 (m, 2H), 2.16-2.07 (m, 2H), 2.01 (d, J=14.6 Hz, 1H), HRMS (m/z) for C₅₁H₆₇ClN₁₁O₁₁ ⁺ [M+H]⁺: calculated 1044.4705, found 1044.4711.

Example 59 Synthesis of XF050-98

To a solution of Intermediate 3 (11.2 mg, 0.02 mmol) in DMSO (1 mL) were added 124(((S )-1-(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenypethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoic acid (13.1 mg, 0.02 mmol, 1.0 equiv), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (1-hydroxy-7-azabenzo-triazole) (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (N-Methylmorpholine) (6.1 mg, 0.06 mmol, 3.0 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford the corresponding product. This product was dissolved in DCM (1mL), before the reaction mixture was treated with TFA (1 mL) for 30 min. After the solvent was evaporated, the residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF050-98 as white solid in TFA salt form (17.4 mg, 79%), ¹H NMR (600 MHz, CD₃OD) δ 8.98 (s, 1H), 8.58 (s, 1H), 7.49-7.41 (m, 6H), 7.36 (dd, J=8.5, 1.8 Hz, 2H), 5.31 (t, J=8.0 Hz, 1H), 5.00 (q, J=7.0 Hz, 1H), 4.62 (s, 1H), 4.59-4.50 (m, 2H), 4.43 (dp, J=4.3, 1.9 Hz, 1H), 4.18 (d, J=13.7 Hz, 1H), 4.13-3.99 (m, 1H), 3.93 (ddt, J=12.8, 9.8, 4.9 Hz, 2H), 3.90-3.78 (m, 3H), 3.75 (dd, J=11.0, 4.0 Hz, 1H), 3.73-3.59 (m, 4H), 3.51-3.46 (m, 2H), 3.46-3.36 (m, 1H), 3.35-3.27 (m, 2H), 3.19 (t, J=5.7 Hz, 2H), 2.48 (s, 3H), 2.36-2.14 (m, 5H), 1.95 (ddd, J=13.3, 9.0, 4.6 Hz, 1H), 1.67-1.53 (m, 4H), 1.50 (d, J=7.0 Hz, 3H), 1.31 (d, J=4.9 Hz, 121-1), 1.19 (d, J=21.4, 7.0 Hz, 3H), 1.04 (s, HRMS (m/z) for C₅₈H₈₂ClN₁₀O₇S⁺ [M+H]⁺: calculated 1097.5772, found 1097.5768.

Example 60 Synthesis of XF050-132

To a solution of Intermediate 2 (12.2 mg, 0.025 mmol) in DMSO (1 mL) added 3-(4-((8-aminooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2.6-dione (9.7 mg, 0.025 mmol, 1.0 equiv), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (7.4 mg, 0.038 mmol, 1.5 equiv), HOAt (1-hydroxy-7-azabenzo-triazole) (5.2 mg, 0.038 mmol, 1.5 equiv), and NMM (N-Methylmorpholine) (7.7 mg, 0.076 mmol 3.0 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford the XF050-132 as white solid in TFA salt term (8.8 mg, 41%). ¹H NMR (600 MHz, CD₃OD) δ 8.57 (s, 1H), 7.51-7.42 (m, 2H), 7.38-7.33 (m, 2H), 7.27 (ddd, J=8.9, 6.9, 1.3 Hz, 1H), 7.21-7.12 (m, 1H), 7.00-6.90 (m, 1H), 5.30 (t, J=7.9 Hz, 1H), 5.13 (dd, J=13.4, 5.1 Hz, 1H), 4.57-4.48 (m, 1H), 4.36 (dd, J=16.7, 1.1 Hz, 1H), 4.27 (d, J=16.7 Hz, 1H), 4.19-4.12 (m, 1H), 3.97-3.46 (m, 8H), 3.44-3.23 (m, 6H), 3.21-3.10 (m, 2H), 3.02-2.81 (m, 2H), 2.68-2.59 (m, 2H), 2.46 (qd, J=13.1, 5.1 Hz, 1H), 2.32-2.24 (m, 1H), 2.21-2.10 (m, 2H), 1.56-1.43 (m, 4H), 1.39-1.24 (m, 8H), 1.24-1.08 (m, 3H). HRMS (m/z) for C₄₅H₅₉ClN₉O₆ ⁺[M+H]⁺: calculated 856.4271, found 856.4277.

Example 61 Synthesis of XF050-133

XF050-133 was synthesized following the standard procedure for preparing XF050-132 from intermediate 2 (12.2 mg, 0.025 mmol), 4-((8-aminooctypoxy)-2-(2,6-dioxopiperidin yl)isoindoline-1,3-dione (10 mg, 0.025 mmol, 1.0 equiv), EDCI (⁷. 4 mg, 0.038 mmol, 1.5 equiv), HOAt (5.2 mg, 0.038 mmol, 1.5 equiv), and NMM (7.7 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF050-133 was obtained as white solid in TFA salt foun (10.2 mg, 47%). ¹H NMR (600 MHz, CD₃OD) δ 8.57 (d, 2.2 Hz, 1H), 7.81-7.74 (m, 1H), 7.49-7.38 (m, 4H), 7.38-7.33 (m, 2H), 5.30 (t, J=8.0 Hz, 1H), 5.10 (dd, J=12.8, 5.5 Hz, 1H), 4.61-4.49 (m, 1H), 4.25-4.13 (m, 3H), 3.98-3.76 (m, 3H), 3.73-3.58 (m, 4H), 3.43-3.36 (m, 1H), 3.35-3.28 (m, 2H), 3,21-3.16 (m, 2H), 2.96-2.82 (m, 1H), 2.79-2.67 (m, 2H), 2.64 (t, J=6.2 Hz, 2H), 2.31-2.24 (m, 1H), 2.23-2.03 (m, 2H), 1.86-1.81 (m, 2H), 1.59-1.45 (m, 4H), 1.46-1.33 (m, 8H), 1.17 (d, J=7.0 Hz, 3H). HRMS (m z) for C₄₅H₅₆ClN₈O₈ ⁺ [M+H]⁺: calculated 871.3904, found 871.3938.

Example 62 Synthesis of XF050-134

XF050-134 was synthesized following the standard procedure for preparing XF050-98 from intermediate 3 (19.2 mg₋0.034 mmol), 942-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonanoic acid (14.7 mg, 0.034 mmol, 1.0 equiv), EDCI (10 mg, 0.051 mmol, 1.5 equiv) 140At (7 mg, 0.051 mmol, 1.5 equiv), and NMM (10.1 mg, 0.1 mmol, 3.0 equiv) in DMSO (1 mL). XF050-134 was obtained as yellow solid in TFA salt form (22.1 mg, 74%). ¹H NMR (600 MHz, CD₃OD) δ 8.57 (d, J=3.9 Hz, 1H), 7.58-7.32 (m, 5H), 7.12-6.90 (m, 2H), 5.30 (t, J=7.9 Hz, 1H), 5.06 (ddd/=12.9, 5.6, 3.4 Hz, 1H), 4.64-452 (m, 1H), 4.24-3.31 (m, 15H), 3.24-3.15 (m, 2H), 2.94-2.79 (m, 2H), 2.76-2.57 (m, 1H), 2.34-2.02 (m, 5H), 1.71-1.49 (m, 4H), 1.41-1.27 (m, 8H), 1.16 (d, J=7.0 Hz, 3H). HRMS (m/z) for C₄₅H₅₇ClN₉O₇ ⁺ [M+H]⁺: calculated 870.4064, found 870.4056.

Example 63 Synthesis of XF050-93

XF056-93 was synthesized following the standard procedure for preparing XE050-132 from intermediate 2 (9.7 mg, 0.02 mmol), 4-(9-aminononyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (8 mg, 0.025 mmol, 1.0 equiv). EDCI (5.8 mg, 0.038 mmol, 1.5 equiv), HOAt (4.1 mg, 0.038 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF056-93 was obtained as white solid in TFA salt form (11.2 mg, 64%). ¹H NMR (600 MHz, CD₃OD) 6. 8.57 (d, J=4.1 Hz, 1H), 7.74-7.68 (m, 2H), 7.65-7.59 (m, 1H), 7.47-7.42 (m, 2H), 7.36 (dd, J=8.4, 1.2 Hz, 2H), 5.31 (t, J=8.0 Hz, 1H), 5.13 (ddd, J=12.8, 5.5, 2.7 Hz, 1H), 4.54 (dd, J=9.4 4.1 Hz, 4, I 7-4.1.0(m, 1H), 3.95-3.86 (m, 2H), 3.82 (s, 1H), 3.71-3.59 (m, 3H), 3.47-3.23 (m, 6E1), 3.16 (t, J=7.2 Hz, 2H), 3.12-3.06 (m, 2H), 2.94-2.84 (m, 1H), 2.80-2.69 (m, 2H), 2.67-2.62 (m, 2H), 2.29 (dd, J=12.8, 7.5 Hz, 1H), 2.21-2.11 (m, 2H), 1.65 (q, J=7.5 Hz, 2H), 1.48 (t, J=7.1 Hz, 2H), 1.36 (s, 5H), 1.30 (d, J=3.4 Hz, 5H), 1.17 (d, J=7.0 Hz, 3H). HRMS (m/z) for C₄₆H₅₈ClN8O₇ ⁺ [M+H]⁺: calculated 869.4112, found 869.4123.

Example 64 Synthesis of XF050-143

XE050-143 was synthesized following the standard procedure for preparing XE050-5 from intermediate 6 (14.2 mng, 0.02 mmol), VHL-C10-COOH (12.8 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF050-143 was obtained as white solid in TFA salt form (13.5 mg, 60%). ¹H NMR (600 MHz, CD₃OD) δ 8.93 (s, 1H), 8.39 (s, 1H), 7.57-7.29 (m, 9H), 6.93 (d, J=3.7 Hz, 1H), 5.01 (dd, J=9.3, 5.8 Hz, 1H), 4.64 (d, J=12.5 Hz, 3H), 4.60-4.47 (m, 3H), 4.35 (d, J=15.4 Hz, 1H), 3.95-3,75 (m, 4H), 3.30-3.24 (m, 9H), 3.13 (td, J=12.2, 5.1 Hz, 1H), 2.68 (ddd, J=15.2₋10.9, 4.7 Hz, 1H), 2.61 (ddd, J=15.0, 10.8₋4.6 Hz, 1H), 2.47 (s, 3H), 2.43-2.32 (m, 4H), 2.32-2.14 (m, 4H), 2.12-2.00 (m, 2H), 1.58 (dp, J=14.4, 7.3, 6.6 Hz, 4H), 1.38-1.25 (m, 12H), 1.03 (s, 9H). HRMS (m/z) for C₅₉H₈₂ClN₁₂O₆S⁺ [M+H]⁺: calculated 1121.5884, found 1121.5898.

Example 65 Synthesis of XF050-144

XF050-144 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (14.2 mg, 002 mmol), VHL-C11-COOH (13.1 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF050-144 was obtained as white solid in TFA salt form (15 mg, 66%). ¹H NMR (600 MHz, CD₃OD) δ 9.06-8.86 (m, 1H), 8.41-8.34 (m, 1H), 7.57-7.27 (m, 9H), 6.94 (q, J=3.9 Hz, 1H), 5.00 (td, J=8.9, 5.1 Hz, 1H), 4.71-4.64 (m, 3H), 4.63-4.46 (m, 3H), 4.35 (dd, J=15.5, 7.0 Hz, 1H), 3.95-3.76 (m, 4H), 3.61-2.89 (m, 10H), 2.65-1.95 (m, 15H), 1.58 (dh, J=15.0, 7.3 Hz, 4H), 1.30 (dd, J=13.9, 6.9 Hz, 14H), 1.09-089 (m, 9H). HRMS (m/z) for C₆₀H₈₄ClN₁₂O₆S⁺ [M+H]⁺: calculated 1135.6041, found 1135.6034.

Example 66 Synthesis of XF050-145

XF050-145 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (14.2 mg, 0.02 mmol), VHL-C12-COOH (13.4 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv, in DMSO (1 mL). XF050-145 was obtained as white solid in TFA salt form (20.2 mg, 88%), ¹H NMR (600 MHz, CD₃OD) S 9.04 (s, 1H), 8.40 (s, 1H), 7.55-7.24 (m, 9H), 7.07-.84 (m, 1H), 5.01 (dd, J=9.3, 5.8 Hz, 1H), 4.71-4.63 (m, 3H), 4.63-4.43 (m, 3H), 4.36 (d, J=15.5 Hz, 1H), 3.95-3.77 (m, 4H), 3.61-2.95 (m, 10H), 2.66 (dddd, J=44.2, 15.0, 10.8, 4.6 Hz, 2H), 2.49 (s, 3H), 2.45-2.14 (m, 8H), 2.12-1.97 (m, 2H), 1.63-1.53 (m, 4H), 1.39-1.19 (m, 1.03 (s, 9H). HRMS (m/z) for C₆₁H₈₆ClN₁₂O₆S⁺ [M+H]⁺: calculated 1149.6197, found 1149.6176.

Example 67 Synthesis of XF050-167

XF050-167 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (23,5 mg, , 0.033 mmol), VHL-C9-COOH Analog (21.2 mg, 0.033 mmol, 1.0 equiv), EDCI (9.6 mg, 0.05 mmol, 1.5 equiv), HOAt (6.8 mg, 0.05 mmol, 1.5 equiv), and NMM (10.1 mg, 0.1 mmol, 3.0 equiv) in DMSO (1 mL). XF050-167 was obtained as white solid in TFA salt form (22.4 mg, 61%). ¹H NMR (600 MHz, CD₃OD) δ 8.95 (d, J=6.3 Hz, 1H), 8.39 (s, 1H), 7.47-7.40 (m, 4H), 7.40-7.30 (m, 5H), 6.94 d, J=3.8 Hz, 1H), 5.08-4.95 (m, 1H), 4.69-4.63 (m, 3H), 4.61-4.52 (m, 1H), 4.46-4.35 (m, 1H), 3.98-3.81 (m, 4H), 3.74 (dd, J=11.0, 4.0 Hz, 1H), 3.64-2.91 (n, 10H), 2.69 (ddd, J=15.1, 10.9, 4.7 Hz, 1H), 2.62 (ddd, dr=15.1, 10.8, 4.7 Hz, 1H), 2.48 (s, 3H), 2.44-2,13 (m, 8H), 2.04 (dq, J=14.7, 3.2, 2.2 Hz, 1H), 1.95 (ddd, J=13,3, 9.1, 4.5 Hz, 1H), 1.66-1.53 (m, 4H), 1.50 (d, J=7.0 Hz, 3H), 1.41-1.23 (m, 10H), 1.04 (s, 9H). HRMS (m/z) for C₅₉H₈₂ClN₁₂O₆S⁺ [M+H]⁺: calculated 1121.5884, found 1121.5869.

Example 68 Synthesis of XF056-33

XF056-33 was synllresized following the standard procedure for preparing XF050-5 from intermediate 6 (12 mg, 0.02 mmol), PML-PEG6-COOI-1 (12.2 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF056-33 was obtained as yellow solid in TFA salt form (10.3 mg, 47%). ¹H NMR (600 MHz, CD₃OD) δ 8.38 (s, 1H), 7.61-7.51 (m, 1H), 7.44-7.28 (m, 4H), 7.07 (dd, J=20.2, 7.8 Hz, 2H), 6.92 (d, J=3,6 Hz, 1H), 5.09-4.98 (m, 2H), 4.65 (d, J=12.4 Hz, 2H), 3.91-3.79 (m, 2H), 3.79-3.69 (m, 4H), 3.69-3.48 (m, 23H), 3.41-3.07 (m, 10H), 2.87 (t, J=14.8 Hz, 1H), 2.80-2.53 (m, 5H), 2.41-2.24 (m, 3H), 2.15 (dd, J=29.7, 13.5 Hz, 2H), 2.04 (d, J=14.7 Hz, 1H). HRMS (m/z) for C₅₃H₇₁ClN₁₁O₁₂ ⁺ [M+H]⁺: calculated 1088.4967, found 1088.4974.

Example 69 Synthesis of XF056-34

XF056-34 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (12.2 mg, 0.02 mmol), PML-PEG8-COOH (14.1 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF056-34 was obtained as yellow solid in TFA salt form (16.1 mg, 68%). ¹11 NMR (600 MHz, CD₃OD) δ 8.39 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.41-7.26 (m, 4H), 7.06 (dd, J=21.5, 7.8 Hz, 2H), 6.93 (d, or=3.7 Hz, 1H), 5.13-5.01 (m, 2H), 4.61 (d, J=14.1 Hz, 2H), 3.94-3.79 (m, 2H), 3.80-3.37 (m, 36H), 3.36-3.00 (m, 101-1.), 2.91-2.83 (m, 1H), 2.79-2.53 (m, 5H), 2.40-2.26 (m, 2H), 2.22-2.00 (m, 3H) HRMS (m/z) for C₅₇H₇₉ClN₁₁O₁₄ ⁺ [M+H]⁺: calculated 1176.5491, found 1176.5475.

Example 70 Synthesis of XF056-35

XF056-35 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (12.2 mg, 0.034 mmol), PML-PEG9-COOH (14.8 mg, 0.02 mmol, 1.0 equiv),

EDCI (5.8 Ing, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.1 mmol, 3.0 equiv) in DMSO (1 iriL). XF056-35 was obtained as yellow solid in TFA salt form (15.9 mg, 65%). ¹H. NMR (600 MHz, CD₃OD) δ 8.40 (s, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.46-7.30 (m, 4H), 7.08 (dd, J=22.3, 7.9 Hz, 2H), 6.94 (d, J=3.6 Hz, 1H), 5.15-4.98 (m, 2H), 4.64 (d, J=14.3 Hz, 2H), 3.87 (q, J=10.9 Hz, 2H), 3.81-3.39 (m, 40H), 3.39-2.96 (m, 10H), 2.87 (td, J=16.2, 14.3, 5.3 Hz, 1H), 2.81-2.57 (m, 5H), 2.41-2.24 (m, 2H), 2.24-1.97 (m, 3H). HRMS (m/z) for C₅₉H₈₃ClN₁₁O₁₅ ⁺ [M+H]⁺: calculated 1220.5753, found 1220.5767.

Example 71 Synthesis of XF056-36

XF056-36 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (12.2 mg, 0.02 mmol) 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oic acid (14.7 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF056-36 was obtained as yellow solid in TFA salt form (16.1 mg, 78%). ¹H NMR (600 MHz, CD₃OD) δ 8.39 (d, J=8.9 Hz, 1H), 7.41-7.32 (m, 6H), 7.00-6.97 (m, 1H), 6.96-6.92 (m, 1H), 5.18 (d, J=13.2 Hz, 1H), 5.05 4.98 (m, 1H), 4.65 (s, 2H), 4.37 (d, J=16.8 Hz, 1H), 4.27 (dd, J=16.8, 3.3 Hz, 1H), 4.07-3.92 (m, 2H), 3.92-3.80 (m, 2H), 3.79-3.68 (m, 2H), 3.67-3.36 (m, 20H), 3.38-3.04 (m, 10H), 3.02-2.80 (m, 2H), 2.67 (dd, J=31.5, 17.7 Hz, 4H), 2.53-2.42 (n, 1H), 2.33 (s, 2H), 2.18 (d, J=14.2 Hz, 1H), 2.10-1.99 (m, 1H). HRMS (m/z) for C₅₁H_(b 69)ClN₁₁O₁₀ ⁺ [M+H]⁺: calculated 1030.4912, found 1030.4945.

Example 72 Synthesis of XF056-37

XF056-37 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (12.2 mg, 0.034 mmol), 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12,15-pentaoxaoctadecan-18-oic acid (11.2 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF056-37 was obtained as yellow solid in TFA salt form (13.4 mg, 64%). ¹H NMR (600 MHz, CD₃OD) δ 8.39 (s, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.36 (q, J=8.4 Hz, 4H), 6.92 (d, J=3.6 Hz, 1H), 5.11 (dd, J=12.8, 5.4 Hz, 1H), 5.01 (d, J=8.2 Hz, 1H), 4.79-4.60 (m, 2H), 4.38 (s, 2H), 3.92 (d, J=4.5 Hz, 2H), 3.88-3.78 (m, 2H), 3.78-3.69 (m, 4H), 3.60 (q, J=17.4, 13.4 Hz, 16H), 3.37-3.02 (m, 10H), 2.88 (t, J=15.1 Hz, 1H), 2.81-2.54 (m, 5H), 2.43-2.25 (m, 2H), 2.22-2.10 (m, 2H), 2.04 (d, J=14.6 Hz, 1H). HRMS (m/z) for C₅₁H₆₆ClN₁₀O₁₂ ⁺ [M+H]⁺: calculated 1045.4545, found 1045.4534.

Example 73 Synthesis of XF056-73

XF056-73 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (12.7 mg, 0.02 mmol), 19-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-4,7,10,13.16-pentaoxanonadecanoic acid (11.4 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF056-73 was obtained as yellow solid in TFA salt form (12.1 mg, 58%). ¹H NMR (600 MHz, CD₃OD) δ 8.40 (s, 1H), 7.80-7.71 (m, 2H), 7.66 (dd, J=6.1, 2.8 Hz, 1H), 7.45-7.26 (m, 4H), 6.95 (d, J=3.6 Hz, 1H), 5.13 (dd, J=12.8, 5.4 Hz, 1H), 5.02 (t, J=7.7 Hz, 1H), 4.66 (s, 2H), 3.86 (q, J=11.8 Hz, 2H), 3.73 (t, J=6.1 Hz, 2H), 3.59 (dt, J=17.2, 4.5 Hz, 17H), 3.51 (t, J=6.4 Hz, 2H), 3.36-3.24 (m, 9H), 3.23-3.06 (m, 3H), 2.94-2.84 (m, 1H), 2.81-2.55 (m, 5H), 2.42-2.25 (m, 2H), 2.16 (t, J=17.3 Hz, 2H), 2.04 (d, J=14.8 Hz, 1H), 1.94 (p, J=6.8 Hz, 2H). HRMS (m/z) for C₅₂H68ClN₁₀O₁₁ ⁺ [M+H]⁺: fit calculated 1043.4752, found 1043.4746.

Example 74 Synthesis of XF061-10

XF061-10 was synthesized following the standard procedure for preparing XF050-5 from intermediate 6 (12.1 mg, 0.02 mmol), 11-(((S)-1-((2R,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecanoic acid (12.5 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF061-10 was obtained as white solid in TFA salt form (9.3 mg, 42%). ¹H NMR (600 MHz, CD₃OD) δ 8.94 (s, 1H), 8.39 (s, 1H), 7.50-7.42 (m, 2H), 7.42-7.32 (m, 7H), 6.94 (d, J=3.7 Hz, 1H), 5.01 (dd, J=9.3, 5.9 Hz, 1H), 4.67 (dd, J=14.4, 8.6 Hz, 2H), 4.57 (dd, J=8.4, 6.5 Hz, 1H), 4.54-4.45 (m, 2H), 4.43 (s, 1H), 4.35 (d, J=15.6 Hz, 1H), 3.99 (dd, J=10.8, 4.9 Hz, 1H), 3.83 (q, J=10.9 Hz, 2H), 3.76-3.71 (m, 1H), 3.58-2.97 (m, 10H), 2.75-2.55 (m, 2H), 2.49 (s, 3H), 2.37 (q, J=7.0, 6.5 Hz, 3H), 2.32-2.23 (m, 2H), 2.23-2.12 (m, 3H), 2.02 (ddd, J=14.6, 9.1, 5.8 Hz, 2H), 1.59-1.13 (m, 14H), 1.07 (s, 9H), HRMS (m/z) for C₅₈H₈₀ClN₁₂O₆S⁺ [M+H]⁺: calculated 1107.5728, found 1107.5745.

Example 75 Synthesis of Intermediate 8

To a suspension of Intermediate 7 (Lapierre et al., 2016) (152 nig, 0.31 mmol) and (3-(3-ethoxy-3-oxopropyl)phenyl)boronic acid (137 mg, 0.62 mmol) in 2.5 mL of dioxane and 1.5 ML of H₂O was added potassium carbonate (128 mg, 0.93 mmol). The mixture was degassed for 5 min, before the catalyst Pd(PPh₃)₄ (18 mg, 5 mol %) was added. After the reaction mixture was stirred at 120° C. for 30 min in microwave, the solvent was removed and the mixture was purified by reverse phase C₁₈ column (10% -100% methanol/0.1% TFA in H₂O) to afford the desired product as white solid in TFA salt form (206 mg, 97% yield), After this product was dissolved in THF (5 mL) and H₂O (2 mL), lithium hydroxide (15 mg, 0.64 mmol) was added. The reaction mixture was stirred at rt overnight. The solvent was removed and the mixture was purified by reverse phase C18 column (10%-100% methanol/0.1% TFA in H₂O) to afford the intermediate 8 as white solid in TFA salt form (193 mg, 99% yield). ¹H NMR (600 MHz, DMSO-d6) 6 8.31 (d, J=8.4 Hz, 1H), 8.05 (dd, J=5.8, 1.7 Hz, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.87 (d, J=1.7 Hz, 1H), 7.84 (dt, J=7.7, 1.5 Hz, 1H), 7.64-7.57 (m, 3H), 7.57-7.51 (m, 4H), 7.50-7.45 (m, 1H), 2.87 (t, J=7.7 Hz, 2H), 2.57 (t, J=7.7 Hz, 2H), 2.07-1.91 (m, 1H), 1.84-1.77 (m, 1H), 1.33 (s, 9H), 1.13-1.08 (m, 4H). ESI-MS (m/z) [M+H]⁺: 605.2878.

Example 76 Synthesis of XF067-1

To a solution of Intermediate 8 (12 mg, , 0.02 mmol) in DMSO (1 mL) were added VHL-PEG1-NH₂ (11.4 mg, 0.02 mmol, 1.0 equiv), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (1-hydroxy-7-azabenzo-triazole) (4.1 mg, 003 mmol, 1.5 equiv), and NMM (N-Methylmorpholine) (6.1 mg, 0.06 mmol, 3.0 equiv). After being stirred overnight at rt, the resulting mixture was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford the corresponding product, After this product was dissolved in DCM (1mL), the reaction mixture was treated with TFA (1 mL) for 30 min. After the solvent was evaporated, the residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF067-1 as white solid in TFA salt form (7.8 mg, 38%). ¹H NMR (800 MHz, CD₃OD) δ 8.88 (s, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.03 (d, J=17.2 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.91-7.78 (m, 5H), 7.72 (d, J=8.0 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.33 (t, J=7.71 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 6.83 (s, 1H), 4.70 (s, 1H), 4.60 (t, J=8.3 Hz, 1H), 4.56-4.47 (m, 2H), 4.32 (d, J=15.4 Hz, 1H), 3.93-3.86 (m, 2H), 3.86-3.78 (m, 2H), 3.48 (dd, J=10.1, 5.3 Hz, 1H), 3.40 (dt, J=9.7, 5.2 Hz, 1H), 3.35-3.29 (m, 2H), 3.00 (t, J=7.6 Hz, 2H), 2.91 (dt, J=14.3, 8.4 Hz, 2H), 2.71 (q, J=11.7, 10.2 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 2.44 (s, 3H), 2.42-2.30 (m, 1H). 2.26 (dd, J=13.2, 7.6 Hz, 1H), 2.15-2.03 (m, 2H). 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1018.4762.

Example 77 Synthesis of XF067-2

XF067-2 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-CH₂CH₂PEG1-NH₂ (15.5 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-2 was obtained as white solid in TFA salt form (14.6 mg, 71%). NMR (800 MHz, CD₃OD) δ 8.96 (s, 1H), 8.31 (dd, J=8.5, 4.3 Hz, 1H), 8.05-7.97 (m, 2H), 7.91-7.85 (m, 2H), 7.84 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.37 (dd, J=23.2, 7.8 Hz, 3H), 7.29 (d, J=7.5 Hz, 1H), 6.84 (t, J=6.9 Hz, 1H), 4.64 (s, 1H), 4.63-4.54 (m, 1H), 4.52-4.44 (m 2H), 4.33 (d, J=15.4 Hz, 1H), 3.88 (d, J=10.9 Hz, 1H), 3.79 (dd, J=11.2, 4.0 Hz, 1H), 3.53 (dq, J=9.8, 4.7, 4.1 Hz, 1H), 3.48 (dt, J=10.1, 5.5 Hz, 1H), 3.38 (ddt, J=26.6, 10.1, 5.3 Hz, 2H), 3.30 (1.1=5.3 Hz, 2H), 298 (1.1=7.6 Hz, 2H), 2.91 (It, J=9.1, 5.81 Hz, 2H), 2.77-2.67 (m, 2H), 2.56 (t, J=7.6 Hz, 2H), 2.47 (s, 3H), 2.41-2,31 (m, 3H), 2.24 (dd, J=13.3, 7.6 Hz, 1H), 2.08 (ddt, J=12.2, 7.9, 3.9 Hz, 2H), 1.01 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1032.4912.

Example 78 Synthesis of XF067-3

XF067-3 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-CH₂PEG2-NH₂ (12.2 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) DMSO (1 mL). XF067-3 was obtained as white solid in TFA salt form (10.5 mg, 49%). ¹H NMR (800 MHz, CD₃OD) δ 8.94 (s, 1H), 8.31 (dd, J=8.3, 3.7 Hz, 1H), 8.02 (dd, J=18.9, 7.4 Hz, 2H), 7.93-7.86 (m, 2H), 7.82 (dd, J=20.7, 8.0 Hz, 3H), 7.72 (d, J=8.0 Hz, 2H), 7.49-7.32 (m, 5H), 7.28 d, J=7.7 Hz, 1H), 6.84 (t, J=6.8 Hz, 1H), 4.73 (s, 1H), 4.62-4.56 (m, 1H), 4.54-4.45 (m, 2H), 4.40-4.32 (m, 1H), 4.01-3.93 (m, 1H), 3.93-3.86 (m, 2H), 3.82 (dd, J=11.2, 4.1 Hz, 1H), 3.66-3.54 (m, 2H), 3.52-3.36 (m, 5H), 3.25 (ddd, J=14.2, 7.3, 3.8 Hz, 1H), 3.02-2.95 (m, 2H), 2.90 (dd, J=12.7, 7.3 Hz, 2H), 2.75-2.69 (m, 2H), 2.59 (dt, J=15.1, 7.8 Hz, 1H), 2.53 (dt, J=14.2, 7.5 Hz, 1H), 2.47 (s, 3H), 2.34 (td, J=11.1, 6.7 Hz, 1H), 2.25 (dd, J=13.4, 7.7 Hz, 1H), 2.09 (ddt, J=25.6, 11.5, 4.7 Hz, 2H), 1.02 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1062.5023.

Example 79 Synthesis of XF067-4

XF067-4 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-CH₂CH₂PEG2—NH2 (16.3 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol 1.5 equiv), HOAt (4.1 mg 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-4 was obtained as white solid in TFA salt form (12.6 mg, 58%). ¹H NMR (800 MHz, CD₃OD) δ 8.95 (d, J=7.0 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.03 (t, J=6.4 Hz, 2H), 7.92-7.86 (m, 2H), 7.83 (dd, J=20.3, 7.9 Hz, 3H), 7.73 (d, J=8.0 Hz, 2H), 7.48-7.38 (m, 4H), 7.40-7.33 (m, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.84 (t, J=7.0 Hz, 1H.), 4.65 (s, 1H), 4.61-4.56 (m, 1H), 4.56-4.49 (m, 2H), 4.40-4.34 (m, 1H), 3.89 (d, J=10.9 Hz, 1H), 3.80 (dd, J=11.1, 4.1 Hz, 1H), 3.72-3.62 (m, 2H), 3.52 (t, J=4.5 Hz, 2H), 3.47 (t, J=5.1 Hz, 2H), 3.40 (t, J=5.4 Hz, 2H), 3.29 (t, J=5.4 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.91 (ddd, J=14.6, 9.0, 5.8 Hz, 2H), 2.72 (ddd, J=13.3, 9.0, 5.9 Hz, 2H), 2.53 (s, 3H), 2.49-2.42 (m, 4H), 2.36-2.30 (m, 1H), 2.23 (dd, J=13.4, 7.6 Hz, 1H), 2.12-2.03 (m, 2H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1076.5164.

Example 80 Synthesis of XF067-5

XF067-5 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 minol), VHL-Cl₂PEG3H₂ (16.9 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NNW (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-5 was obtained as white solid in TFA salt form (16.4 mg, 74%). ¹H NMR (800 MHz, CD₃OD) δ 8.93 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 8.03 (t, J=6.9 Hz, 2H), 7.91 (s, 7.88 (d, J=7.8 Hz, 1H), 7.83 (dd, J−19.6, 7.8 Hz, 3H), 7.73 (d, J=5.3 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 7.37 (t, J=7.7 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 6.84 (t, J=6.9 Hz, 1H), 4.70 (s, 1H), 4.59 (t, J=8.6 Hz, 1H), 4.52 (d, J=4.3 Hz, 2H), 4.37 (d, J=15.4 Hz, 1H), 4.06-3.96 (m, 4H), 3.88 (d, J=11.0 Hz, 1H), 3.81 (dd, J=11.2, 4.0 Hz, 1H), 3.69-3.62 (m, 41), 3.57 (q, J=4.5 Hz, 2H), 3.47 (t, J=L 7 Hz, 2H), 3.38 (i, J=5.5 Hz, 2H), 3.27 (t, J=5.4 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.91 (dt, J=14.3, 8.7 Hz, 2H), 2.76 2.68 (m, 2H), 2.53 (t, J=7.6 Hz, 2H), 2.47 (s, 3H), 2.38 2.29 (m, 1H), 2.25 (dd, J=12.8, 7.9 Hz, 1H), 2.14-2.04 (m, 2H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1106.5268.

Example 81 Synthesis of XF067-6

XF067-6 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol) VHL-CH₂CH₂PEG3-NH₂ (17.2 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) DMSO (1 mL). XF067-6 was obtained as white solid in TFA salt form (12.2 mg, 54%). ¹H NMR (800 MHz, CD₃OD) δ 8.95 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.04 (t, J=6.5 Hz, 2H), 7.92 (s, 7.88 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.42 (d, J=7.8 Hz, 2H), 7.37 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.84 (t, J=6.9 Hz, 1H), 4.65 (s, 1H), 4.58 (t, J=8.5 Hz, 1H), 4.54 (d, J=15.4 Hz, 1H), 4.52-4.50 (m, 4.40-4.34 (m, 1H), 3.90 (d, J=10.9 Hz, 1H), 3.81 (dd, J=11.1, 4.1 Hz, 1H), 3.74-3.66 (m, 2H), 3.63-3.55 (m, 4H), 3.53 (t, J=4.7 Hz, 2H), 3.44 (t, J=4.7 Hz, 2H), 3.39 (d, J=5.4 Hz, 2H), 3.28 (t, J=5.5 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 2.91 (dt, J=14.4, 8.6 Hz, 2H), 2.72 (ddd, J=13.7, 9.1, 6.0 Hz, 2H), 2.60-2.51 (m, 3H), 2.51-2.43 (m, 4H), 2.37-2.32 (m, 1H), 2.24 (dd, J=13.4, 7.6 Hz, 1H), 2.09 (dtd, J=15.6, 11.0, 10.1, 5.2 Hz, 2H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1120.5423.

Example 82 Synthesis of XF067-7

XF067-7 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-CH₂CH₂PEG4-NH₂ (14.2 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-7 was obtained as white solid in TFA salt form (122 mg, 52%). ¹NMR (800 MHz, CD₃OD) d 8.92 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 8.08-8.00 (m, 2H), 7.92 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.83 (dd, J=12.6, 7.9 Hz, 3H), 7.73 (d, J=8.0 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.37 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.61 Hz, 1H), 6.83 (t, J=6.9 Hz, 1H), 4.65 (s, 1H), 4.62-4.47 (m, 3H), 4.37 (d, J=15.4 Hz, 1H), 3.90 (d, J=10.9 Hz, 1H), 3.81 (dd, J=11.1, 4.1 Hz, 1H), 3.70 (ddq, J=28.0, 10.3, 5.4 Hz, 2H), 3.64-3.55 (m, 8H), 3.52 (t, J=4.6 Hz, 2H), 3.44 (t, J=4.7 Hz, 2H), 3.39 (t, J=5.5 Hz, 2H), 3.28 (t, J=5.4 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 2.95-2.87 (m, 2H), 2.77-2.68 (m, 2H), 2.59-2.51 (m, 3H), 2.51-2.44 (m, 414), 2.33 (dd, J=13.4, 8.2 Hz, 1H), 2.24 (dd, J=13.2, 7.7 Hz, 1H), 2.12-2.04 (m, 2H), 1.04 (s, 9H). ESI-MS m/z) [M+H]⁺: 164.5673.

Example 83 Synthesis of XF067-8

XF067-8 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-CH₂CH₂PEG5—NH2 (18.9 mg, 002 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-8 was obtained as white solid in TFA salt form (13.9 mg, 58%). ¹H NMR (800 MHz, CD₃OD) δ 8.91 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.92 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.83 (dd, J=12.5, 7.9 Hz, 3H), 7.73 (d, J=8.0 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.42 (d, J=7.8 Hz, 2H), 7.38 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.83 (11=6.9 Hz, 1H), 4.66 (s, 1H), 4.63-4.53 (m, 2H), 4.51 (s, 1H), 4.37 (d, J=15.4 Hz, 1H), 3.90 (d, J=10.9 Hz, 1H), 3.81 (dd, J=11.1, 4.1 Hz, 1H), 3.72 (dtt, J=21.3, 10.3, 5.4 Hz, 2H), 3.59 (ddt, J=15.3, 10.8, 4.4 Hz, 12H), 3.52 (t, J=4.6 Hz, 2H), 3.44 (t, J=4.6 Hz, 2H), 3.39 (t, J=5.5 Hz, 2H), 3.27 (t, J=5.5 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 2.95-2.88 (m, 2H), 2.78-2.69 (m, 2H), 2.60-2.51 (m, 3H), 2.51-2.41 (m, 4H), 2.34 (dq, J=13.7, 7.8, 5.9 Hz, 1H), 2.24 (dd, J=13.1, 7.7 Hz, 1H), 2.13-2.03 (m, 2H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1208.5948.

Example 84 Synthesis of XFO₆₇-9

XF067-9 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-C1-NH₂ (14.3 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-9 was obtained as white solid in TFA salt form (11.7 mg, 60%). ¹HNMR (800 MHz, CD₃OD) δ 8.88 (s, 1H), 8.30 (d, .I-8.4 Hz, 1H), 8.07-7.98 (m, 2H), 7.92 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.83-7.80 (m, 3H), 7.73 (s, 2H), 7.48 (d, J=7.9 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 6.83 (t, J=6.9 Hz, 1H), 4.64 (s, 1H), 4.61-4.53 (m, 2H), 4.52 (d, J=4.4 Hz, 1H), 4.36 (d, J=15.4 Hz, 11-0, 3.89-3.79 (m, 4H), 3.03 (1, J=7.8 Hz, 2H), 2.91 (tt, J=9.3, 5.6 Hz, 2H), 2.72 (dq, J=14.3, 9.3, 7.6 Hz, 2H), 2.63 (1.J=7.8 Hz, 2H), 2.46 (s, 3H), 2.34 (dd, J=10.8, 6.3 Hz, 1H), 2.25 (dd, J=13.3, 7.6 Hz, 1H), 2.16-2.02 (m, 2H), 1.03 (s, 9H). ESI-MS (m/z ) [M+H]⁺: 974.4486.

Example 85 Synthesis of XF067-10

XF067-10 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-C2-NH₂ (14.6 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (I mL). XF067-10 was obtained as white solid in TFA salt form (13.5 mg, 68%). 1H NMR (800 MHz, CD₃OD) δ 8.93 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.02 (dd, J=11.7, 7.3 Hz, 2H), 7.94-7.79 (m, 5H), 7.72 (d, J=8.0 Hz, 2H), 7.45 (d, J=7.9 Hz, 2H), 7.40 (d, J=79 Hz, 2H), 7.38-7.35 (m, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.84 (t, J=6.9 Hz, 1H) 4.61-4.46 (m, 4H), 4.35 (d, J=15.4 Hz, 1H), 3.91 (d, J=10.9 Hz, 1H), 3.80 (dd, J=11.1, 4.1 Hz, 1H), 3.42-3.35 (m, 2H), 2.99 (t, J=7.6 Hz, 2H), 295-2.88 (m, 2H), 2.76-2.64 (m, 2H), 2.51 (t, J=7.6 Hz, 2H), 2.47 (s, 3H), 2.40-2.28 (m, 3H), 2.23 (dd, J=13.3, 7.5 Hz, 1H), 2.09 (tdd, J=17.2, 10.8, 6.6 Hz, 2H), 1.01 (s, 9H). ESI-MS (m/z) [M+H]⁺: 988.4638.

Example 86 Synthesis of XF067-11

XF067-11 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-C3-NH₂ (14.8 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol., 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-11 was obtained as white solid in TFA salt form (13.8 mg, 69%). ¹H NMR (800 MHz, CD₃OD) δ 8.94 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.03 (dd, J=11.1, 7.1 Hz, 1H), 792 (s, 1H), 7.88 (d, J=7.8 Hz, IFI), 7.85 (d, J=7.7 Hz, 1H), 7.81(d, J=8.1 Hz, 2H), 7.73 (d, J=8.1 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.37 (q, J=7.9 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 6.84 (t, J=7.0 Hz, 1H), 4.60-4.56 (m, 2H), 4.55 (s, 4.52 (d, J=32 Hz, 1H), 4.37 (d, J=15.4 Hz, 1H), 3.90 (d, J-10.9 Hz, 1H), 3.81 (dd, J=11.1, 4.1 Hz, 1H), 3.16-3.10 (m, 2H), 3.02-2.98 (m, 2H), 2.94-2.89 (m, 2H), 2.72 (td, J=14.3, 11.7, 7.2 Hz, 2H), 2.53 (t, J=7.5 Hz, 2H), 2.48 (s, 3H), 2.39-2.29 (m, 1H), 2.28-2.21 (m, 1H), 2.17-2.02 (m, 4H), 1.73-1.64 (m, 2H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1002.4804.

Example 87 Synthesis of XF067-12

XF067-12 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-C4-NH₂ (11.3 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol. 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-12 was obtained as white solid in TFA salt form (15.5 mg, 76%). ¹H NMR (800 MHz, CD₃OD) δ 8.93 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.03 (dd, J-8.4, 4.5 Hz, 2H), 7.92 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.85 d, J=7.5 11z, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.77-7.67 (m, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.44-7.33 (m, 3H), 7.32-7.25 (m, 1H), 6.84 (t, J=7.0 Hz, 1H), 4.60 (s, 1H), 4.60-4.49 (m, 3H), 4.37 (d, J=15.4 Hz, 1H), 3.90 (d, J=10.9 Hz, 1H), 3.81 (dd, J=11.1, 4.1 Hz, 1H), 3.11 (t, J=6.9 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.92 (dt, J=14.5, 8.6 Hz, 2H), 2.72 (dt, J=13.2, 8.0 Hz, 2H), 2.56-2.50 (m, 2H), 2.48 (s, 3H), 2.37-2.30 (m, 1H), 2.26-2.21 (m, 1H), 2.19-2.14 (m, 1H), 2.13-2.05 (m, 2H), 1.50-1.41 (m, 2H), 1.40-1.32 (m, 2H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1016.4976.

Example 88 Synthesis of XF067-13

XF067-13 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-05—NI-1₂ (11.6 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol. 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 ML). XF067-13 was obtained as white solid in TFA salt form (13.6 mg, 66%). ¹H NMR(800 MHz, CD₃OD) δ 8.97 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.03 (t, J=6.8 Hz, 2H), 7.92 (s, 1H), 7.88 (dd, J=18.0, 7.8 Hz, 2H), 7.83-7.79 (m, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.8 Hz, 2H), 7.38 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 6.85 (t, J=7.0 Hz, 1H), 4.62 (s, 1H), 4.61-4.57 (m, 1H), 4.55 (d, J=15.4 Hz, 1H), 4.52 (s, 1H), 4.38 (d, J=15.4 Hz, 1171), 3.91 (d, 10.9 Hz, 1H), 3.81 (dd, J=11.1, 4.1 Hz, 1H), 3.09 (td, J=7.5, 2.5 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.92 (ddd, J=14.7, 11.9, 7.2 Hz, 2H), 2.77-2.69 (m, 2H), 2.52 (d, J=7.5 Hz, 2H), 2.48 (s, 3H), 2.39-2.30 (m, 1H), 2.24 (dd, Jr=13.4, 7.6 Hz, 1H), 2.19-2.16 (m, 1H), 2.15-2.01 (m, 3H), 1.46 (dp, J=15.1, 7.1 Hz, 2H), 1.35 (p, J=7.5 Hz, 2H), 1.20-1.14 (m, 2H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1030.5111.

Example 89 Synthesis of XF067-14

XF067-14 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-C6-NH₂ (11.8 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 inmol, 3.0 equiv) in DMSO (1 ml-). XF067-14 was obtained as white solid in TFA salt form (8.4 mg, 40%). 1H NMR (800 MHz, CD₃OD) δ 8.9:5 (s, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.04 (q, J=3.7 Hz, 2H), 7.93-7.87 (m, 2H), 7.86 (d, J=7.6 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.43 (d./=7.8 Hz, 2H), 7.41-7.35 (m, 1H), 7.29 1=7.5 Hz, 1H), 6.85 (t, J=6.9 Hz, 1H), 4.63 (s, 1H), 4.60 (t, J=8.0 Hz, 1H), 4.57-4.49 (m, 2H), 4.38 (d, J=15.4 Hz, 1H), 3.92 (d, J=10.9 Hz, 1H), 3.82 (dd, J=11.1, 4.1 Hz, 1H), 3.08 (t, J=7.1 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.92 (dt, J=14.6, 8.3 Hz, 2H), 2.76-2.67 (m, 2H), 2.52 (d, J=7.5 Hz, 2H), 2.48 (s, 3H), 2.34 (tq, J=16.4, 10.0, 7.7 Hz, 1H), 2.28-2.03 (m, 5H), 1.53-1.44 (m, 2H), 1.34 (p, J=7.1 Hz, 2H), 1.21-1.12 (m, 4H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1044.5284.

Example 90 Synthesis of X F067-15

XF067-15 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-C7—NI-I2 (16 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-I5 was obtained as white solid in TFA salt form (9.6 mg, 45%). ¹H NMR (800 MHz, CD₃OD) δ 8.96 (s, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.07-8.00 (m, 2H), 7.92 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.86 (d, J=7.61 Hz, 1H). 7.82 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.1 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.8 Hz, 2H), 7.37 (t, J=7.7 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.84 (t, J=6.9 Hz, 1H), 4.64 (s, 1H), 4.59 (t, J=8.3 Hz, 1H), 4.56 (d, J=15.4 Hz, 1H), 4.52 (d, J=4.2 Hz, 1H), 4.38 (d, J=15.4 Hz, 1H), 3.91 (d, J=11.0 Hz, 1H), 3.82 (dd, J=11.1, 4.1 Hz, 1H), 3.08 (q,=6.7 Hz, 2H), 2.99 (t, J=7.4 Hz, 2H), 2.92 (tt, J=9.3, 5.8 Hz, 2H), 2.75-2.68 (m, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.49 (s, 3H), 2.37-2.31 (m, 1H), 2.28-2.21 (m, 2H), 2.18 (dt, J=14.6, 7.5 Hz, 1H), 2.14-2.04 (m, 2H), 1.57-1.45 (m, 2H), 1.33 (p, J=7.1 Hz, 2H), 1.24-1.09 (m, 6H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1058.5425.

Example 91 Synthesis of XF067-16

XF067-16 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL:-C₈-NH₂ (12.4 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-16 was obtained as white solid in TFA salt form (8.6 mg, 40%). ¹HNMR (800 MHz, CD₃OD) δ 8.92 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.07-8.00 (m, 2H), 7.92 (s, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.83 (dd, J=14.8, 7.8 Hz, 3H), 7.77-7.69 (m, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.8 Hz, 2H), 7.37 (t, J=7.7 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.83 (t, J=6.9 Hz, 1H), 4.65 (s, 1H), 4.60 (t, J=8.1 Hz, 4_57-4.50 (m, 2H), 4.38 (d, J=15.4 Hz, 1H), 3.92 (d, J=10.9 Hz, 1E1), 3.82 (dd, J=11.1. 4.1 Hz, 1H), 3.08 (t, J=7.1 Hz, 2H), 2.99 (t, J=7.4 Hz, 2H), 2.92 (dt, J=14.6, 6.1 Hz, 2H), 2.76-2.67 (m, 2H), 2.52 (t, J=7.6 Hz, 2H), 2.48 (s, 3H), 2.34 (tqd, J=10.8, 6.8, 3.3 Hz, 1H), 2.23 (ddq, J=29.7, 14.6, 7.3 Hz, 3H), 2.10 (dddd, J=23.5, 17.8, 10.5, 5.8 Hz, 2H), 1.54 (qq, J=13.9, 7.0 Hz, 2H), 1.32 (dp, J=13.9, 7.1 Hz, 2H), 1.27-1.09 (m, 8H), 1.05 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1072.5598.

Example 92 Synthesis of XF067-17

XF067-17 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-C9-NH₂ (16.5 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-17 was obtained as white solid in TFA salt form (7.3 mg, 34%). ¹H NMR (800 MHz, CD₃OD) δ 8.92 (s, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.09-8.00 (m, 2H), 7.92 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.82 (t, J=7.9 Hz, 3H), 7.73 (d, J=8.1 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 7.37 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 6.83 (t, J=6,9 Hz, 1H), 4.65 (s, 1H), 4.62-4.51 (m, 3H), 4.38 (d, 15.4 Hz, 1H), 3.92 (d, J=10.9 Hz, 1H), 3.83 (dd, J=11.1. 4.1 Hz, 1H), 3.08 (t, J=7.1 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.92 (q, J=9.8, 7.7 Hz, 2H), 2.72 (dt, J=14.0, 8.5 Hz, 2H), 2.54-2.46 (m, 5H). 2.38 2.31 (m, 1H), 2.30-2.18 (m, 3H), 2.15-2.02 (m, 2H), 1.56 (ddq, J=20.4, 13.5, 6.8 Hz, 2H), 1.32 (t, J=7.1 Hz, 2H), 1.29-1.23 (m, 2H), 1.23-1.19 (m, 2H), 1.18-1.14 (m, 2H), 1.14-1.11 (m, 4H), 1.06 (s, 9H), ESI-MS (m/z) [M+H]⁺: 1086.5721.

Example 93 Synthesis of XF067-18

XF067-18 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), VHL-C10-NH₂ (16.5 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-18 was obtained as white solid in TFA salt form (8.7 mg, 37%). ¹H NMR (800 MHz, CD₃OD) δ 8.92 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 15 8.05-8.01 (m, 2H), 7.93 (s, 1H), 7.89 (d, J=7.7 F1z, 1H), 7.82 (t, J=6.9 F1z, 3H), 7.75-7.68 (m, 2H), 7.48 (d, J=7.9 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 7.37 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 6.83 (t, J=6.9 Hz, 1H), 4.65 (s, 1H), 4.62-4.58 (m, 1H), 4.56 (d, J=15.5 Hz, 1H), 4.52 (d, J=3.8 Hz, 1H), 4.41-4.35 (m, 1H), 3.92 (d, J=10.9 Hz, 1H), 3.85-3.79 (m, 1H), 3.08 (t, J=7.1 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.92 (It, J=9.4, 5.6 Hz, 2H), 2.77-2.68 (m, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.49 (s, 3H), 2.35 (tt, J=10.8, 5.8 Hz, 1H), 2.29 (dt, f=14.9, 7.7 Hz, 1H), 2.24 (dt, J=14.8, 7.8 Hz, 2H), 2.14-2.02 (m, 2H), 1.64-1.52 (m, 2H), 1.37-1.23 (m, 6H), 1.22-1.10 (m, 8H), 1.05 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1110.5912.

Example 94 Synthesis of XF067-19

XF067-19 was synthesized following the standard procedure for preparing X.F067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-PEG1-NH₂ (9.4 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-19 was obtained as yellow solid in TFA salt form (10.9 mg, 64%). ¹H NMR (800 MHz, CD₃OD) δ 8.22 (d, J=8.4 Hz, 1H), 8.03 (d, J=6,2 Hz, 1H), 8.02-7.96 (m, 1H), 7.92 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.79 (t, J=8.0 Hz, 3H), 7.77-7.67 (m, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.32 (q, J=7.8 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 6.98-6.93 (m, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.82 (t, J=7.0 Hz, 1H), 4.93 (dd, J=21.3, 10.7, 7.4, 3.5 Hz, 1H), 3,48-3.37 (m, 3H), 3.35-3,32 (m, 1H), 3.33-3.23 (m, 2H), 3.27-3.25 (m, 2H), 3.01 (h, J=6.8 Hz, 2H), 2.90 (dt, J=14.1. 8.1 Hz, 2H), 2.70 (ddd, J=18.2, 13.5, 6.6 Hz, 3H), 2.67-2.53 (m, 4H), 2.32 (ddd, J=16.4, 10.8, 6.3 Hz, 1H), 2.07 (dp, J=16.5, 7.9 Hz, 1H), 1.96 (dd, J=12.5, 6.4 Hz, 1H). ESI-MS (m/z) [M+H]⁺: 847.3668.

Example 95 Synthesis of XF067-20

XF067-20 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-PEG2-NH₂ (10.3 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 ing, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol. 3.0 equiv) in DMSO (1 mL), XF067-20 was obtained as yellow solid in TFA salt form (13.4 mg, 75%). ¹H NMR (800 MHz, CD₃OD) δ 8.28 (d, J=8.4 Hz, 1H), 8.01 (dd, J=14.4, 7.2 Hz, 2H), 7.92-7.85 (m, 2H), 7.80 (t, J=7.8 Hz, 3H), 7.71 (d, J=8.0 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 6.98 (t, J=8.3 Hz, 2H), 6.81 (t, J=6.9 Hz, 1H), 5.01 (dd, J=12.8, 5.4 Hz, 1H), 3.64 (t, J=5.2 Hz, 2H), 3.55 (t, J=4.4 Hz, 2H), 3.48 (t, J=4.5 Hz, 2H), 3.41 (dt, J=10.5, 5.4 Hz, 4H), 3.30 (q, J=5.8 Hz, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.94-2.87 (m, 2H), 2.81 (ddd, J=18.1, 13.7, 5.3 Hz, 1H), 2.75-2.67 (m, 3H), 2.68-2.62 (m, 1H), 2.52 (t, J=7.5 Hz, 2H), 2.33 (qt, J=10.5, 6.4 Hz, 1H), 2.06 (ddq, J=18,7, 12.1, 6.9, 6.1 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 891.3945.

Example 96 Synthesis of XF067-21

XF067-21 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-PEG3-NH₂ (11.2 mg, 0.02 mmol 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-21 was obtained as yellow solid in TFA salt form (11.9 mg, 64%). 1H NMR (800 MHz, CD₃OD) δ 8.28 (d, J=8.4 Hz, 1H), 8.02 (dd, J=14.8, 7.2 Hz, 2H), 7.90 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.9 Hz, 3H), 7.71 (d, J=8.0 Hz, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.07-6.94 (m, 2H), 6.81 (t, J=6.9 Hz, 1H), 5.01 (dd, 12.7, 5.3 Hz, 1H), 3.66 (t, J=5.2 Hz, 2H), 3.62 (p, J=4.5, 3.8 Hz, 4H), 3.55 (t, J=4.5 Hz, 2H), 3.46 (t, J=4.5 Hz, 2H), 3.41 (dt, J=21.3, 5.3 Hz, 4H), 3.27 (t, J=5.4 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.94-2.87 (m, 2H), 2.82 (ddd, J=18.2, 13.7, 5.3 Hz, 1H), 2.74-2.62 (m, 4H), 2.54 (t, J=7.6 Hz, 2H), 2.34 (qd, J=104, 5.3 Hz, 1H), 2.07 (ddt, J=17.7, 11.6, 6.9 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 935.4187.

Example 97 Synthesis of XF067-22

XF067-22 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-PEG4-NH₂ (11.3 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 006 mmol, 3.0 equiv) in DMSO (1 mL). XF067-22 was obtained as yellow solid in TFA salt form (9.5 mg, 49%). ¹H NMR (800 MHz, CD₃OD) δ 8.29 (s, 1H), 8.02 (d, J=8.0 Hz, 2H), 7.91 (s, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.71 (t, J=11.1 Hz, 3H), 7.49 (t, J=7.9 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.04-6.99 (m, 2H), 6.76 (s, 1H), 5.01 (dd, J=12.6, 5.3 Hz, 1H), 3.71-3.59 (m, 8H), 3.59-3.56 (m, 2H), 3.52 (t, J=4.6 Hz, 2H), 3.43 (q, J=4.9 Hz, 4H), 3.38 (t, J=5.4 Hz, 2H), 3.27 (t, J=5.4 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.91 (dd, J=13.1, 7.1 Hz, 2H), 2.86-2.78 (m, 1H), 2.73-2.65 (m, 4H), 2.54 (t, J=7.6 Hz, 2H), 2.33 (d, J=10.2 Hz, 1H), 2.10-2.03 (m, 2H). ESI-MS (m/z) [M+H]⁺: 979.4463.

Example 98 Synthesis of XF067-23

XF067-23 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-PEG5-NH₂ (12.2 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-23 was obtained as yellow solid in TFA salt form (11.3 mg, 55%). ¹H NMR (800 MHz, CD₃OD) δ 8.30 (d, J=8.3 Hz, 1H), 8.08-7.97 (m, 2H), 7.91 (s, IFI), 7.88 (d, J=7.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 3H), 7.72 (d, J=8.0 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 7.02 (dd, J=17.2, 7.9 Hz, 2H), 6.82 (t, J=6.9 Hz, 1H), 5.02 (dd, J=12.6, 5.4 Hz, 1H), 3.68 (t, J=5.1 Hz, 2H), 3.66-3.54 (m, 12H), 3.52 (q, J=4.6 Hz, 2H), 3.44 (dt, J=9.4, 4.8 Hz, 4H), 3.38 (t, J=5.4 Hz, 2H), 3.26 (t, J=5.4 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.91 (dq, J=14.4, 8.5, 7.2 Hz, 2H), 2.82 (ddd, J=18.0, 13.6, 5.3 Hz, 1H) 2.75-2.64 (m, 4H), 2.54 (t, J=7.6 Hz, 2H) 2.34 (tt, J=12.1, 6.4 Hz, 1H), 2.08 (dq, J=12.6, 7.5, 6.6 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 1023.4738.

Example 99 Synthesis of XF067-24

XF067-24 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-C₂-NH₂ (8.6 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-24 was obtained as yellow solid in TFA salt form (10.5 mg, 65%). ¹H NMR (800 MHz, CDsOD) δ 8.22 (d, J=8.4 Hz, 1H), 8.03 (d, J=6.2 Hz, 1H), 7.99-7.93 (m, 1H), 7.91 (s, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.80 (t, J=7.1 Hz, 3H), 7.66 (d, J=8.0 Hz, 2H), 7.38-7.33 (m, 1H), 7.31-7.25 (m, 2H), 6.92-6.87 (m, 1H), 6.82 (t, J=6.9 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 5.01 (dd, J=12.7, 5.4 Hz, 1H), 3.27 (Dept, J=6.5, 5.8 Hz, 2H), 3.16-3.10 (m, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.92 (dt, J=11.1, 7.2 Hz, 2H), 2.82 (ddd, J=18.2, 13.7, 5.3 Hz, 1H), 2.75-2.63 (m, 4H), 2.53 (t, J=7.3 Hz, 2H), 2.33 (qt, J=10.6, 6.3 Hz, 1H), 2.07 (dq, J=13.7, 7.8, 6.7 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 803.3417.

Example 100 Synthesis of XF067-25

XF067-25 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-C₃—NH2 (8.9 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-25 was obtained as yellow solid in TFA salt form (16.3 mg, 99%). ¹H NMR (800 MHz, CD₃OD) δ 8.20 (d, J=8.4 Hz, 1H), 8.03 (d, J=6.2 Hz, 1H), 7.93 (s, 1H), 7.92-7.86 (m, 1H), 7.80 (dq, J=19.8, 7.5, 6.0 Hz, 4H), 7.68 (d, J=8.0 Hz, 2H), 7.39 (t, J=7.7 Hz, 1H), 7.35-7.28 (m, 2H), 6.87 (d, J=7.1 Hz, 1H), 6.83 (q, J=6.6 Hz, 1H), 6.62 (d, J=8.5 Hz, 1+1), 5.00 (dd, J=12.8, 5.5 Hz, 1H), 3.18 (pt, J=12.8, 6.6 Hz, 2H), 3.03 (t, J=7.1 Hz, 2H), 2.92 (dt, J=14.5, 8.2 Hz, 2H), 2.87-2.79 (m, 3H), 2.77-2.66 (m, 4H), 2.56 (t, J=7.0 Hz, 2H), 2.34 (dtd, J=16.2, 10.3, 6.5 Hz, 1H), 2.13 (dt, J=12.6, 6.2 Hz, 1H), 2.07 (dq, J=16.4, 8.3 Hz, 1H), 1.54 (p, J=6.8 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 817.3578.

Example 101 Synthesis of XF067-26

XF067-26 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-C₄-NH₂ (9.2 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-26 was obtained as yellow solid in TFA salt form (10.5 mg, 63%). ¹H NMR (800 MHz, CD₃OD) δ 8.23 (d, J=8.3 Hz, 1H), 8.02 (d, J=6.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.90-7.85 (m, 2H), 7.78 (dd, J=21.0, 7.8 Hz, 3H), 7.66 (d, J=8.0 Hz, 2H), 7.38 (t, J=7.7 Hz, 2H), 7.31 (d, J=7.6 Hz, 1H), 6.97-6.91 (m, 1H), 6.82 (q, J=9.2, 6.9 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 5.09-5.03 (m, 1H), 3.10 (t, J=6.6 Hz, 2H), 3.01 (t, J=7.1 Hz, 2H), 2.94-2.83 (m, 5H), 2.80-2.67 (m, 4H), 2.54 (t, J=7.1 Hz, 2H), 2.33 (qt, J=10.3, 6.4 Hz, 1H), 2.13 (dt, J=12.6, 5.8 Hz, 1H), 2.06 (4.1=14.0, 8.4 Hz, 1H), 1.32 (dq, J=11.4, 6.6 Hz, 2H), 1.24 (q, 7.6 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 831.3721.

Example 102 Synthesis of XF067-27

XF067-27 was synthesized following the standard procedure for preparing XF ₋67-1 from intermediate 8 (12 mg, 0.02 mmol), PML-05—NT-12 (9.7 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-27 was obtained as yellow solid in TFA salt form (11.1 mg, 66%). ¹H NMR (800 MHz, CD₃OD) δ 8.27 (d, J=8.4 Hz, 1H), 8.01 (dd, J=10.1, 7.0 Hz, 2H), 794-7.88 (m, 2H), 7.79 (d, J=8.1 Hz, 2H), 7.71 (d, J=7.7 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.41 (t, J=7.7 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 6.94-6.88 (m, 1H), 6.79 (t, J=7.0 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.02 (dd, J=12.7, 5.4 Hz, 1H), 3.11 (td, dr=7.2, 2.3 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.97 (t, J=7.3 Hz, 2H), 2.93-2.87 (m, 2H), 2.86-2.79 (m, 1H), 2.77-2.64 (m, 4H), 2.54 (t, J=7.2 Hz, 2H), 2.33 (dq, J=11.8, 6.1, 5.2 Hz, 1H), 2.07 (tt, J=13.3, 6.0 Hz, 2H) 1.38-1.29 (m, 4H), 1.11 (q, J=7.8 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 845.3867.

Example 103 Synthesis of XF067-28

XF067-28 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-C₆-NH₂ (8.2 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-28 was obtained as yellow solid in TFA salt form (10,9 mg, 63%). ¹H NMR (800 MHz, CD₃OD) δ 8.28 (d, J=8.3 Hz, 1H), 8.05-7.99 (m, 7.93-7.88 (m, 2H), 7.80 d, J=8.0 Hz, 2H), 7.70 (dd, J=27.6, ⁷. 9 Hz, 3H), 7.46 (t, J=7.8 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 6.95 (d_(—J=)7.1 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.78 (t, J=6.9 Hz, 1H), 5.07 (dd, J=12.6, 5.4 Hz, 1H), 3.09 (t, J=6.8 Hz, 2H), 3.04 (t, J=7.3 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.94-2.83 (m, 3H), 2.80-2.68 (m, 4H), 2.54 (t, J=7.2 Hz, 2H), 2.33 (qt, J=10.3, 6.4 Hz, 1H), 2.13 (dq, J=12.7, 6.6, 5.5 Hz, 1H), 2.07 (dq, J=13.6, 8.4, 7.8 Hz, 1H), 1.38 (p, J=7.4 Hz, 2H), 1.31 (q, J=7.3 Hz, 2H), 1.18-1.14 (m, 2H), 1.08 (q, J=7.9 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 859.4043.

Example 104 Synthesis of XF067-29

XF067-29 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-C₇-NH₂ (10 mg, 0.02 mmol, 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-29 was obtained as yellow solid in TFA salt form (15.2 mg, 87%). ¹H NMR (800 MHz, CD₃OD) δ 8.29 (d, J=8.4 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 8.00 (d, J=6.3 Hz, 1H), 7.93-7.88 (m, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.74 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.01-6.96 (m, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.78 (t, J=6.9 Hz, 1H), 5J05 (dd, J=12.7, 5.4 Hz, 1H), 3.14-3.05 (m, 4H), 3.00 (t, J=7.2 Hz, 2H), 2.94-2.82 (m, 3H), 2.78-2.67 (m, 4H), 2.53 (t, J=7.2 Hz, 2H), 2.33 (dtd, J=16.3, 10.4, 6.5 Hz, 1H), 2.13-2.03 (m, 2H), 1.44 (p, J=7.4 Hz, 2H), 1.29 (p, J=7.2 Hz, 2H), 1.19 (p, J=7.3 Hz, 2F1), 1.13-1.03 (m, ESI-MS (m/z) [M+H]⁺: 873.4186.

Example 105 Synthesis of XF067-30

XF067-30 was synthesized following the standard procedure for preparing XF067-1 from intermediate 8 (12 mg, 0.02 mmol), PML-C₈—NH2 (10.2 mg, 0.02 mmol 1.0 equiv), EDCI (5.8 mg, 0.03 mmol, 1.5 equiv), HOAt (4.1 mg, 0.03 mmol, 1.5 equiv), and NMM (6.1 mg, 0.06 mmol, 3.0 equiv) in DMSO (1 mL). XF067-30 was obtained as yellow solid in TFA salt form (11.1 mg, 63%). ¹H NMR (800 MHz, CD₃OD) δ 8.32-8.26 (m, 1H), 8.05-7.98 (m, 2H), 7.92-7.87 (m, 2H), 7.85-7.78 (m, 2H), 7.76 (d, J=7.7 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.40-7.33 (m, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.02-6.97 (m, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.79 (t, J=7.0 Hz, 1H), 5.06 (dd, J=12.8, 5.3 Hz, 1H), 3.17 (t, J=7.2 Hz, 2H), 3.09 (t, J=7.0 Hz, 2H), 3.00 (t, J=7.3 Hz, 2H), 2.94-2.82 (m, 3H), 2.79-2.66 (m, 4H), 2.53 (t, J=7.3 Hz, 2H), 2.34 (qt, J=10.4, 6.3 Hz, 1H), 2.13-2.04 (m, 2H), 1.49 (p, J=7.3 Hz, 2H), 1.31 (p, J=7.2 Hz, 2H), 1.26 (q, J=7.4 Hz, 2H), 1.15 (q, J=7.3 Hz, 2H), 1.09 (ddt, J=21.5, 14.5, 7.8 Hz, 4H). ESI-MS (m/z) [M+H]⁺: 887.4367.

Example 106 Synthesis of Intermediate 9

To a suspension of Intermediate 7 (156.4 mg, 0.32 mmol) and (3-(cyanomethyl)phenyl)boronic acid (102 mg, 0.64 mmol) in dioxane (2.5 mL) and 1⁻120 (1.5 mL) was added potassium carbonate (144 mg, 093 mmol). The mixture was degassed for 5 min, before the catalyst Pd(PPh₃)₄ (19 mg, 5 mol %) was added. After the reaction mixture was stirred at 120° C. for 30 nun in microwave, the solvent was removed and the mixture was purified by reverse phase C₁₈ column (10% -100% methanol/0,1% TFA in H₂O) to afford the desired product as white solid in TFA salt form (206 mg, 97% yield). After this product was dissolved in 5 mL of methanol, the catalyst Raney nickel and NH3^(.)1420 (a few drops) were added. The reaction was stirred at rt for 1 h, before the mixture was filtered through a pad of Celite. After the filtrate was concentrated, the resulting residue was purified by reverse phase C₁₈ column (10% -100% methanol/0.1% TFA in H₂O) to afford the intermediate 9 as yellow solid in TFA salt form (272.5 ing, 43% yield). ¹H NMR (500 MHz, CD₃OD) δ 8.31 (d, J=8.4 Hz, 1H), 8.09-7.93 (m, 514), 7.81-7.68 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.46 (t, J=7.7 Hz, 11-1.), 7.36 (dt, J=7.7, 1.4 Hz, 1H), 6.77 (t, J=6.9 Hz, 1H), 3.25 (1.1=7.7 Hz, 2H), 3.06 (t, J=7.7 Hz, 2H), 2.61 (ddd, J=12.2, 6.2, 2.5 Hz, 2H), 2.55 (d, J=13.8 Hz, 2H), 2.20 (s, 1H), 2.00 (s, 1H), 1.56-1.06 (m, 9H). ESI-MS (m/z) [M+H]⁺: 576.3062.

Example 107 Synthesis of XF067-31

To a solution of Intermediate 9 (9.3 mg, 0.016 mmol) in DMSO (1 mL) were added VHL-PEG1-CH₂COOH (8.3 mg, 0.016 mmol, 1.0 equiv), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (1-hydroxy azabenzo-triazole) (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (N-Methylmorpholine) (4.8 mg, 0.048 mmol. 3.0 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford the corresponding product. After this product was dissolved in DCM (1mL), the reaction mixture was treated with TFA (1 mL) for 30 min. After the solvent was evaporated, the residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF067-31 as white solid in TFA salt form (7.8 mg, 38%). ¹H NMR (800 MHz CD₃OD) δ 8.88 (d, J=25.3 Hz, 1H), 8.43-7.64 (m, 10H), 7.61-7.20 (m, 611), 6.83 (t, J=25.0 Hz, IFI), 4.77-4.27 (m, 5H), 4.20-3.78 (m, 6H), 3.70-3.43 (m, 2H), 292 (t, J=21.5 Hz, 6H), 2.56-1.98 (m, 7H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1004.4613.

Example 108 Synthesis of XF067-32

XF067-32 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-PEGI-CH₂CH₂-CO₂H (9.3 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-32 was obtained as white solid in TFA salt form (9.1 mg, 55%). ¹H NMR (800 MHz, CD₃OD) δ 8.95 (s, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.1 Hz, 2H), 796 (s, 1H), 7.88 (dd, J=22,4, 7.7 Hz, 2H), 7.82 (d, j=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.48-7.35 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 6.85 (t, J=6.9 Hz, 1H), 4.64 (s, 1H), 4.58 (t, J=8.4 Hz, 1H), 4.56-4.49 (m, 2H), 4.39-4.34 (m, 1H), 3.89 (d, J=10.9 Hz, 1H), 3.80 (dd, J=11.1, 4.0 Hz, 1H), 3.69-3.63 (m, 3E1), 3.60 (dt, J=10.2, 5.7 Hz, 1H), 3.48 (t, J=7.6 Hz, 2H), 2.90 (dt, J=19.6, 7.5 Hz, 4H), 2.73 (dt, J=12.4, 7.7 Hz, 2H), 2.52-2.38 (m, 7H), 2.35 (s, 1H), 2.24 (dd, J=13.3, 7.6 Hz, 1H), 2.09 (dtd, J=12.8, 8.8, 4.4 Hz, 2H), 1.03 (s, 9H). ESI-MS (m/z) for [M+H]⁺: 1032.4904.

Example 109 Synthesis of XF067-33

XF067-33 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-PEG2-C₁-T₂-CO₂I-I (9.4 mg, 0.016 mmol,1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-33 was obtained as white solid in TFA salt form (6.2 mg, 37%), ¹H NMR (800 MHz, CD₃OD) δ 8.90 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 8.07-8.02 (m, 2H), 7.97 (s, 1H), 7.90 (d .T=7.8 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.82 (d, J=7.9 Hz, 2H), 7.73 (d, J=8.1 Hz, 2H), 7.39-7.35 (m, 5H), 7.31 (d, J=7.5 Hz, 1H), 6.85 (t, J=6.9 Hz, 1H), 4.73 (s, 1H), 4.61 (t, J=8.5 Hz, 1H), 4.53 (s, 1H), 4.41 (d, J=15.3 Hz, 1H), 4.35 (d, J=15.4 Hz, 1H), 4.05-3.88 (m, 6H), 3.86-3.81 (m, 1H), 3.70-3.50 (m, 5H), 2.96-2.86 (m, 4H), 2.75-2.69 (m, 2H), 2.45 (s, 3H), 2.38-2.31 (m, 1H), 2.27 (dd, J=13.0, 7.6 Hz, 1H), 2.12-2.04 (m, 2H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1048.4877.

Example 110 Synthesis of XF067-34

XF067-34 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-PEG2-CH₂CH₂-CO₂H (9.9 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-34 was obtained as white solid in TFA. salt form (9.1 mg, 53%), ¹14 NMR (800 MHz, CD₃OD) δ 8.94 (s, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.05 (t, J=7.7 Hz, 2H), 7.96 (s, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.86 (d .T=7.6 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 7.40 (dt, J=26.0, 8.4 Hz, 3H), 7.31 (d, J=7.5 Hz, 1H), 6.85 (t, J=7.0 Hz, 1H), 4.65 (s, 1H), 4.58 (t, J=8.2 Hz, 1H), 4.54 (d, J=15.4 Hz, 1H), 4.50 (s, 1H), 4.37 (d, J=15.4 Hz, LH), 3.89 (d, J=10.9 Hz, 1H), 3.80 (dd, J=11.1, 4.1 Hz, 1H), 3.68 (dhept, J=11.5, 5.2 Hz, 4H), 3.58-3.51 (m, 4H), 3.48 (1J=7.5 Hz, 2H), 2.90 (dt, J=24.4, 7.01 Hz, 4H), 2.76-2.70 (m, 2H), 2.53 (dt, =13.6, 6.8 Hz, 1H), 2.49-2.39 (m, 6H), 2.34 (dd, J=11.3, 6.1 Hz, 1H), 2.23 (dd, J=13.3, 7.6 Hz, 1H), 2.09 (ddt, J=17.0, 12.3, 6.3 Hz, 2H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1076.5189.

Example 111 Synthesis of XF067-35

XF067-35 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-PEG3-CH₂-CO₂H (10.1 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 Int). XF067-35 was obtained as white solid in TFA salt form (6.8 mg, 39%). 41 NMR (800 MHz, CD₃OD) δ 8.91 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.05 (dd, J=8.3, 4.2 Hz, 2H), 7.99 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.84 (dd, J=29.9, 7.9 Hz, 3H), 7.76-7.69 (m, 2H), 7.45 (d, J=7.9 Hz, 2H), 7.40 (dp, J=15.2, 7.7 Hz, 3H), 7.30 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 4.70 (s, 1H), 4.62-4.47 (m, 3H), 4.35 (d, J=15.3 Hz, 1H), 4.09-3.84 (m, 5H), 3.80 (dd, J=11.1., 4.0 Hz, 1H), 3.70-3.58 (m, 8H), 3,58-3.7 (m, 2H), 2.91 (dt, J=15.0, 7.1 Hz, 4H), 2.73 (q, J=12.1, 9.9 Hz, 2H), 2.47 (s, 3H), 2.38-2.30 (m, 1H), 2.23 (dd, J=13.3, 7.6 Hz, 1H), 2.13-2.02 (m, 2H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1092.5135.

Example 112 Synthesis of XF067-36

XF067-36 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-PEG3-CH₂CH₂-CO₂H (10.6 mg, 0.016 mmol, 1.0 equiv) EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 int). XF067-36 was obtained as white solid in TFA salt form (8.3 mg, 46%). ¹⁻1-1 NMR (800 MHz, CD₃OD) δ 8.93 ts, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.05 (t, J=8.1 Hz, 2H), 7.97 (s, 1H), 7.90 (d, J :=7.8 Hz, 7.84 (dd, J=25.3, 7.8 Hz, 3H), 7.74 (d, J=8.0 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 7.41 (It, J=15.4, 6.9 Hz, 3H), 7.31 (d, J=7.5 Hz, 1H), 6.84 (t, J=7.0 Hz, 1H), 4.64 (s, 1H), 4.59-4.47 (n, 3H), 4.37 (d, J=15.4 Hz, 1H), 3.89 (d, J=10.9 Hz, 1H), 3.80 (dd, J=11.1, 4.0 Hz, 1H), 3.74-3.63 (m, 4H), 3.63-3.51 (m, 8H), 3.48 (t, J=7.5 Hz, 2H), 2.94-2.86 (m, 4H), 2.76-2.70 (m, 2H) 2.58-2.51 (m, 1H), 2.49-2.39 (m, 6H), 2.38-2.31 (m, 1H), 2.23 (dd, J=13.1, 7.7 Hz, 1H), 2.12-2.03 (m, 2H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1120.5442.

Example 113 Synthesis of XF067-37

XF067-37 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-PEG4-CH7CH₂-CO₂H (11.3 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-37 was obtained as white solid in TFA salt form (8.4 mg, 45%). ¹H NMR (800 MHz, CD₃₀D) 6 8.92 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.05 (dd, J=11.9, 7.2 Hz, 2H), 7.98 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.45-7.37 (m, 3H), 7.31 (d, J=7.51 Hz, 1H), 6.84 (t, J=7.01 Hz, 1H), 4.64 (s, 1H), 4.59-4.48 (m, 3H), 4.37 (d, J=15.4 Hz, 1H), 3.89 (d, J=10.9 Hz, 1H), 3.81 (dc. J=11.1, 4.0 Hz, 1H), 3.73-3.63 (m, 4H), 3.63-3.50 (m, 12H), 3.48 (t, J=7.5 Hz, 2H), 2.93-2.87 (n, 4H), 2.79-2.68 (m, 2H), 2.57-2.40 (m, 7H), 2.33 (q, J=8.7. 7.0 Hz, 1H), 2.23 (dd, J=13.3, 7.6 Hz, 1H). 2.12-2.04 (m, 2H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1164.5682.

Example 114 Synthesis of XF067-38

XF067-38 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-PEGS-CH₂-CO₂H (11.6 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-38 was obtained as white solid in TFA salt form (9.7 mg, 51%). ¹H NMR (800 MHz, CD₃OD) δ 8.95 (d, J=13.9 Hz, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.11-7.98 (m, 3H), 7.92 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.74 (d, J=7.9 Hz, 2H), 7.49-7.36 (m, 5H), 7.31 (d, J=7.6 Hz, 1H), 6.86 (t, J=7.0 Hz, 1H), 4.69 (s, 1H), 4.62-4.50 (m, 3H), 4.37 (d, J=15.4 Hz, 1H), 4.05-3.91 (m, 4H), 3.88 (d, J=11.2 Hz, 1H), 3.82 (dd, J=11.2, 3.9 Hz, 1H), 3.73-3.50 (m, 18H), 2.91 (d, J=7.7 Hz, 4H), 2.74 (q, J=12.0, 10.3 Hz, 2H), 2.48 (s, 3H), 2.37-2.31 (m, 1H), 2.25 (dd, J=13.4, 7.7 Hz, 1H), 2.14-2.02 (m, 2H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1180.5672.

Example 115 Synthesis of XF067-39

XF067-39 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 ing, 0.016 mmol), VHL-PEGS-CH₂CH₂-CO₂H (12 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-39 was obtained as white solid in TFA salt form (10.6 mg, 55%). NMR (800 MHz, CD₃OD) 6. 8.96 (s, 1H), 8.33 (d, J=8.5 Hz, 1H), 8.05 (dd, J=12.2, 7.2 Hz, 2H), 8.00 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.83 (d, J=8.1 Hz, 2H) 7.75 (d, J=8.0 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.39 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 6.85 (t, J=6.9 Hz, 1H), 4.65 (s, 1H), 4.61-4.47 (m, 3H), 4.37 (d, J=15.4 Hz, 1H), 3.89 (d, J=10.9 Hz, 1H), 3.81 (dd, J=11.1, 4.0 Hz, 1H), 3.70-3.62 (m, 4E1), 3.62-3.51 (m, 161-1), 3.49 (t, J=7.6 Hz, 2H), 2.90 (dt, J=27.1, 6.6 Hz, 4H), 2.74 (q, J=12.4, 10.6 Hz, 2H), 2.57-2.51 (m, 1H), 2.49 (s, 3H), 2.43 (h, J=5.6 Hz, 3H), 2.38-2.30 (m, 1H), 2.24 (dd, J=13.3, 7.7 Hz, 1H), 2.14-2.03 (m, 2H), 1.03 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1208.5978.

Example 116 Synthesis of XF067-40

XF067-40 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-C2-CO₂H (8.5 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, , 0.024 mmol, 1.5 equiv) HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, , 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-40 was obtained as white solid in TFA salt form (10.6 mg, 67%). ¹H NMR (800 MHz, CD₃OD) δ 8.97 (s, 1H), 8.32 d, J=8.4 Hz, 1H), 8.04 (t, J=7.8 Hz, 2H), 7.95 (s, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.84 (dd, J=27.5, 7.8 Hz, 3H), 7.73 (d, J=8.1 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.41-7.35 (m, 1H), 7.30 (d, J=7.6 Hz, 1H), 6.84 (t, J=6.9 Hz, 1H), 4.64-4.47 (m, 4H), 4.38 (d, J=15.4 Hz, 1H), 3.90 (d, J=10.9 Hz, 1H), 3.85-3.74 (m, 1H), 3.51-3.41 (m, 2H), 2.96-2.85 (m, 4H), 2.77-2.69 (m, 2H), 2.58 (dt, J=14.3, 7.1 Hz, 1H), 2.54-2.41 (m, 6H), 2.39-2.31 (m, 1H), 2.23 (dd, 13.2, 7.7 Hz, 1H), 2.13-2.03 (m, 2H), 1.07-0.99 (m, 9H). ESI-MS (m/z) [M+H]⁺: 988.4659.

Example 117 Synthesis of XF067-41

XF067-41 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-C3-CO₂H (8.7 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-41 was obtained as white solid in TFA salt form (8.3 mg, 52%). ¹H NMR (800 MHz, CD₃OD) δ 8.93 (d, J=29.3 Hz, 1H), 8.30 (dd, J=25.1, 8.4 Hz, 1H), 8.04 (t, J=6.3 Hz, 2H), 7.97 (s, 1H), 7.88 (dd, J=23.2, 7.7 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.44-7.36 (m, 3H), 7.29 (d, J=7.5 Hz, 1H), 6.85 (s, 1H), 4.63-4.46 (m, 4H), 4.37 (d.T=15.4 Hz, 1H), 3.92 (d, J=10.9 Hz, 1H), 3.83 (dd, J=11.1, 4.1 Hz, 1H), 3.48 (hept, J=6.9, 6.2 Hz, 2H), 2.91 (dq, J=19.5, 7.9 Hz, 4H), 2.76-2.70 (m, 2H), 2.47 (s, H), 2.37 (ddt, J=28.9, 13.6, 5.6 Hz, 1H), 2.29-2.14 (m, 5H), 2.14-2.03 (m, 2H), 1.85 (p, J=7.5 Hz, 2H), 1.03 (s, ESI-MS (m/z) [M+H]⁺: 1002.4811.

Example 118 Synthesis of XF067-42

XF067-42 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-C4-CO₂H (8.9 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-42 was obtained as white solid in TFA salt form (6.7 mg, 41%). ¹H NMR (800 MHz, CD₃OD) δ 8.93 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.09-8.00 (m, 2H), 7.96 (s, 1H), 7.90 (d, 1 7.8 Hz, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.39 (q, J=7.9 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.84 (t, J=6.9 Hz, 1H), 4.63 (s, 1H), 4.61-4.50 (m, 3H), 4.37 (d, J=15.4 Hz, 1H), 3.91 (d, J=10.9 Hz, 1H), 3.82 (dd, J=11.1, 4.1 Hz, 1H), 3.47 (t, J=7.5 Hz, 2H), 2.98-2.83 (m, 4H), 2.77-2.70 (m, 2H), 2.54-2.45 (m, 31-1.), 2.39-2.30 (m, 1H), 2.28-2.12 (m, 5H), 2.13-2.05 (m, 2H), 1.58 (q, J=9.0 Hz, 4H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1016.4956.

Example 119 Synthesis of XF067-43

XF067-43 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-CS-CO₂H (9.2 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol. 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv). and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-43 was obtained as white solid in TFA salt form (8.6 mg, 52%). ¹H NMR (800 MHz, CD₃OD) δ 8.94 (s, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.09 7.99 (m, 2H), 7.96 (s, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.74 (dI-8.1 Hz, 2H), 7.48 (d, J=7.9 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 7.39 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 6.85 (t, J=6.9 Hz, 1H), 4.63 (s, 1H), 4.61-4.49 (m, 3H), 4.40-4.34 (m, 1H), 3.91 (d, J=10.9 Hz, 1H), 3.81 (dd, J=11.1, 4.1 Hz, 1H), 3.47 (q, J=7.8 Hz, 2H), 2.91 (dq, J=19.4, 8.3, 7.5 Hz, 4H), 2.72 (dt, J=14.0, 8.4 Hz, 2H), 2.49 (s, 3H), 2.34 (dp, J=21.6, 7.1 Hz, 1H), 2.23 (t4.1=12.3, 5.8 Hz, 2H), 2.16 (dt/=19.4, 7.4 Hz, 3H), 2.13-2.04 (m, 2H), 1.54 (dp, J=18.7, 7.2 Hz, 4H), 1.27 (p, J=9.1, 8.4 Hz, 2H), 1.04 (s, 9H). ESI-MS (m/z) [M H]⁺: 1030.5126.

Example 120 Synthesis of XF067-44

XF067-44 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-C6-CO₂H (9.4 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-44 was obtained as white solid in TFA salt form (8.4 mg, 50%). ¹H NMR (800 MHz, CD₃OD) δ 8.95 (s, 1H), 8.32 (d, ,I=8.3 Hz, 1H), 8.04 (h, J=4.3 Hz, 2H), 7.96 (s, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.77-7.70 (m, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.8 Hz, 2H), 7.41-7.35 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.85 (t, J=6.9 Hz, 1H), 4.64 (s, 1H), 4.62-4.48 (m, 3H), 4.38 (d, J=15.5 Hz, 1I4), 3.92 (d, ,I=10.9 Hz, 1H), 3.82 (dd, J=11.1, 4.1 Hz, 1H), 3.47 (t, J=7.4 Hz, 2H), 2.89 (dhept, J=16.3, 8.1 Hz, 4H), 2.72 (dt, J=14.1, 8.5 Hz, 2H), 2.53-2.44 (m, 3H), 2.39-2.28 (m, 1H), 2.27-2.03 (m, 7H), 1.59-1.49 (m, 4H), 1.26 (p, J=3.8 Hz, 4H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1044.5289.

Example 121 Synthesis of XF067-45

XF067-45 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol) VHL-C7-CO₂H (9.6 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-45 was obtained as white solid in TFA salt form (5.4 mg, 32%). 1H NMR (800 MHz, CD₃OD) δ 8.93 (s, 1H), 8.32 (d, J=7.4 Hz, 1H), 8.07-7.67 (m, 9H), 7.55m, 6H), 6.84 (s, 1H), 4.70-4.45 (m, 414), 4.38 (dd, J=15.3, 6.4 Hz, 1H), 3.91 (t, J=8.7 Hz, 1H), 3.82 (p, J=4.2 Hz, 1H), 3.47 (q, J=7.6 Hz, 2H), 2.97-2.84 (m, 4H), 2.72 (dq, J=13.8, 8.0 Hz, 2H), 2.49 (s, 3H), 2.34 (s, 1H), 2.30-2.01 (m, 7H), 1.54 (dd, J=13.8, 7.0 Hz, 4H), 1.32-1.11 (m, 6H), 1.15-0.94 (m, 9H). ESI-MS (m/z) [M+H]1058.5451,

Example 122 Synthesis of XF067-46

XF067-46 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VtIL-C₈-CO₂1-1 (9.8 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-46 was obtained as white solid in TFA salt form (5.3 mg, 31%). 1H NMR (800 MHz, CD₃OD) δ 8.94 (s, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.05 (dd, J=8.4, 4.7 Hz, 2H), 7.96 (s, 1H), 7.90 (d, J=7.7 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.74 (d, f=8.0 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.8 Hz, 2H), 7.38 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 4.68-4.62 (m, 1H), 4.63-4.47 (m, 3H), 4.38 (d, J=15.4 Hz, 1H), 3.92 (d, J=10.9 Hz, 1H), 3.82 (dd, J=11.1, 4.1 Hz, 1H), 3.47 (q, J=7.7 Hz, 2H), 2.94-2.86 (m, 4H), 2.72 (q, J=12.3, 10.3 Hz, 2H), 2.49 (d, J=4.6 Hz, 3H), 2.34 (d, J=10.5 Hz, I_H), 2.25 (ddt, J=36.7, 14.8, 7.5 Hz, 3H), 2.19-2.03 (m, 4H), 1.56 (ddd, J=32.8, 14.0, 7.1 Hz, 4H), 1.23 (s, 8H), 1.05 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1072.5593.

Example 123 Synthesis of XFO₆₇-47

XF067-47 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), VHL-C9-CO₂H (10 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-47 was obtained as white solid in LTA salt form (8.4 mg, 48%). 1H NMR (800 MHz, CD₃OD) δ 8.92 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.2 Hz, 2H), 7.96 (s, 1H), 7.90 (d, J=7.6 Hz,1H), 7.82 (t, J=8.4 Hz, 3H), 7.73 (d, J=8.1 Hz, 2H), 7.55-7.35 (m, 5H), 7.30 (d, J=7.4 Hz, 1H), 6.82 (s, 1H), 4.65 (s, 1H), 4.61-4.47 (m, 3H), 4.38 (d, J=15.4 Hz, 1H), 3.92 (d, J=10.7 Hz, 1H), 3.82 (dd, J=11.1, 4.0 Hz, 1H), 3.48 (t, J=7.4 Hz, 2H), 2.98-2.84 (m, 4H), 2.78-2.66 (m, 2H), 2.49 (s, 3H), 2.40-2.20 (m, 5H), 2.20-2.01 (m, 3H), 1.68-1.45 (m, 4H), 1.22 (s, 10H), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1086.5765.

Example 124 Synthesis of XF067-48

XF067-48 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-C₁-CO₂H (5.3 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-48 was obtained as yellow solid in IFA salt form (5.3 mg, 42%). ¹H NMR (800 MHz, CD₃OD) δ 8.28 (d, J=8.4 Hz, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.88 (d, J=5.7 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H), 7.73 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.27-7.20 (m, 2H), 6.86 (d, J=7.2 Hz, 1H), 6.77 (t, J=6.8 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.06 (dd, J=12.8, 5.5 Hz, 1H), 3.91 (s, 2H), 3.58 (kept, J=6.7 Hz, 2H), 2.94 2.85 (m, 5H), 2.79-2.67 (m, 4H), 2.34-2.30 (m, 1H), 2.16-1.98 (m, 2H). ESI-MS (m/z) [M+H]⁺: 789.3244.

Example 125 Synthesis of XF067-49

XF067-49 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg 0.016 mmol), PML-C₂-CO₂H (5.5 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 nig, 0.024 mmol. 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-49 was obtained as yellow solid in TFA salt form (7.4 mg, 58%). ¹H NMR (800 MHz, CD₃OD) δ 8.26 (d, J=8.4 Hz, 1H), 8.05-7.99 (m, 2H), 7.94 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.82-7.78 (m, 3H), 7.68 (d, J=8.0 Hz, 2H), 7.43-7.33 (m, 2H), 7.28 (d, J=7.5 Hz, 1H), 6.97 (d, J=7.1 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.85-6.76 (m, 1H), 5.01 (dd, J=12.5, 5.3 Hz, 1H), 3.48 (q, J=7.9 Hz, 4H), 2.94-2.88 (m, 2H), 2.87 (t, J=7.3 Hz, 2H), 2.80 (ddd, J=19.2, 14.3, 5.4 Hz, 1H), 2.71 (td, J=14.1, 11.7, 7.2 Hz, 2H), 2.70-2.61 (m, 2H), 2.46 (t, J=6.7 Hz, 2H), 2.37-2.30 (m, 1H), 2.06-2.03 (m, 2H). ESI-MS (m/z) [M H]⁺: 803.3419.

Example 126 Synthesis of XF067-50

XF067-50 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-C₃-CO₂H (5.7 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-50 was obtained as yellow solid in TFA salt form (8.5 mg, 65%). ¹H NMR (800 MHz, CD₃OD) δ 8.24 (d, J=8.4 Hz, 1H), 8.03 (d, J=6.2 Hz, 1H), 8.00-795 (m, 7.85 (d, J=7.8 Hz, 1H), 7.79 (dd, 14.6, 7.7 Hz, 3H), 7.68 (t, J=6.1 Hz, 2H), 7.37 (dt, J=16.3, 7.7 Hz, 2H), 7.31 (d, J=7.5 Hz, 1H), 6.94-6.87 (m, 1H), 6.82 (t, J=6.9 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 4.99 (di, J=13.5, 6.3 Hz, 1H), 3.53 (p, J=6.7 Hz, 2H), 3.07 (t, J=7.3 Hz, 2H), 2.91 (p, J=8.3, 7.8 Hz, 4H), 2.79 (ddd, J=18.3, 13.8, 5.1 Hz, 1H), 2.76-2.62 (m, 4H), 2.35-2.30 (m, 1H), 2.22 (t, J=7.2 Hz, 2H), 2.06 (s, 2H), 1.79 (p, J=7.3 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 817.3576.

Example 127 Synthesis of XF067-51

XF067-51 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-C₄-CO₂H (6 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-51 was obtained as yellow solid in TFA salt form (7.6 mg, 57%). ¹H NMR (800 MHz, CD₃OD) d 8.25 (d, J=8.4 Hz, 1H), 8.02 (dd, J=24.9, 7.3 Hz, 2H), 7.94 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.79 (dd, J=11.5, 7.6 Hz, 3H), 7.68 (d, J=8.0 Hz, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 6.98-6.93 (m, 1H), 6.81 (dd, J=20.2, 7.7 Hz, 2H), 5.08-5.02 (m, 1H), 3.53 (t, J=7.1 Hz, 2H), 3.06 (t, J=7.1 Hz, 2H), 2.95-2.82 (m, 5H), 2.79-2.68 (m, 4H), 2.33 (tq, J=16.4, 7.0 Hz, 1H), 2.18 (t, J=7.2 Hz, 2H), 2.12 (dd, J=12.5, 5.8 Hz, 1H), 2.10-2.02 (m, 1H), 1.58 (p, J=7.3 Hz, 2H), 1.44 (p, J=7.3 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 831.3715.

Example 128 Synthesis of XF067-52

XF067-52 was synthesized following* the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-05-CO₂H (6.2 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv). HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-52 was obtained as yellow solid in TFA salt form (9.2 mg, 68%). NMR (800 MHz, CD₃OD) δ 8.28 (d, J=8.4 Hz, 1H), 8.03 (dd, J=12.4, 7.3 Hz, 2H), 7.95 (s, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.75 (d, J=7.6 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 6.97-6.91 (m, 1H), 6.84-6.78 (m, 2H), 4.99 (dd, ,I=12.7, 5.4 Hz, 1H), 3.52 (t, J=7.1 Hz, 2H), 3.07 (t, J=7.2 Hz, 2H), 2.94-2.86 (m, 5H), 2.79 (ddd, J=18.2, 13.6, 5.3 Hz, 1H), 2.74-2.70 (m, 2H), 2.67 (dtd, J=31.0, 13.2, 11.6, 4.3 Hz, 2H), 2.33 (dt, J=11.5, 6.0 Hz, 1H), 2.16 (t, J=7.2 Hz, 2H), 2.10-2.01 (m, 1H), 1.55 (q,=7.5 Hz, 2H), 1,47 (q, J=7.41 Hz, 2H), 1.27-1.22 (m, 2H). ESI-MS (m/z) +H +: 845.3876.

Example 129 Synthesis of XF067-53

XF067-53 was synthesized following the standard procedure for preparing XI; 067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-C₆-CO₂H (6.4 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-53 was obtained as yellow solid in TFA salt form (8.3 mg, 60%), ¹H NMR (800 MHz, CD₃OD) δ 8.29 (d, J=8.4 Hz, 1H), 8.02 (dd, J 12.1, 7.0 Hz, 2H), 7.94 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), ⁷. 80 d, J=8.0 Hz, 2H), 7.75 (d, =7.7 Hz, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 6.96 (d, J=7.1 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 6.79 (s, 1H), 5.06 (dd, J=12.6, 5.4 Hz, 1H), 3.52 (t, J=7.1 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 2.94-2.83 (m, 5H), 2.78-2.68 (m, 4H), 2.33 (dq, J=16.3, 8.6, 7.9 Hz, 1H), 2.17-2.08 (m, 3H), 2.07-2.05 (m, 1H), 1.53 (q, J=7.5 Hz, 2H), 1.46 (p, J=7.3 Hz, 2H), 1.26 (q, J=7.5 Hz, 2H), 1.21 (q, J=7.7 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 859.4025.

Example 130 Synthesis of XF067-54

XF067-54 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-C₇-CO₂H (6.6 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 tng, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol. 1.5 equiv), and NMM (4.8 tng, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-54 was obtained as yellow solid in TFA salt form (9.2 mg, 66%). ¹H NMR (800 MHz, CD OD) δ 8.31 (d, J=8.3 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 8.01 (d, J=6.2 Hz, 1H), 7.94 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.79 (dd, J=26.9, 7.8 Hz, 3H), 7.71 (d, J=8.0 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 6.99 (t, J=5.9 Hz, 1H), 694 (d, J=8.5 Hz, 1H), 6.80 (t, J=6.9 Hz, 1H), 5.07-5.01 (m, 1H), 3.51 (t, J=7.2 Hz, 2H), 3.16 (t, J=7.2 Hz, 2H), 2.91 (h, J=7.5 Hz, 4H), 2.84 (ddd, J=18.0, 13.6, 5.3 Hz, 1H), 2.77-2.66 (m, 4H), 2.34 (tq, J=15.8, 7.4, 7.0 Hz, 1H), 2.14 (t, J=7.4 Hz, 2H), 2.12-2.05 (m, 2H), 1.51 (qt, J=1 1. 1, 5.5 Hz, 4H), 1.26 (q, J=7.4 Hz, 2H), 1.21 (tq,=11.0, 6.8, 6.0 Hz, 4H). EST-MS (m/z) [M+H]⁺: 873,4187.

Example 131 Synthesis of XF067-55

XF067-55 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-CH₂CH₂-PEG1-CO₂H (6.2 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-55 was obtained as yellow solid in TFA salt form (7.7 mg, 57%). 1H NMR (800 MHz, CD₃OD) δ 8.28 (d, J=8.3 Hz, 1H), 8.02 (dd, J=11.4, 7.2 Hz, 2H), 7.97 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.80 (dd, J=8.0, 5.0 Hz, 3H), 7.70 (d, J=8.0 Hz, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.28 (d, J=7.5 Hz, 1H), 6.96 (t, J=7.6 Hz, 2H), 6.82 (t, 6.9 Hz, 1H), 4.88-4.77 (m, 1H), 3,76-3.70 (m, 2H), 3.58 J=5.1 Hz, 2H), 3.49 (t, J=7.5 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 2.89 (dt, J=15.1, 11.1 Hz, 511), 2.73-2.69 (m, 2H), 2.62-2.52 (m, 2H), 2.45 (t, J=5.8 Hz, 2H), 2.37-2.29 (m, 1H), 2.10-2.04 (m, 1H), 1.89 (d, J=12.6 Hz, 1H). ESI-MS m/z) [M+H]⁺: 847.3673,

Example 132 Synthesis of XF067-56

XF067-56 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-CH₂CH₂-PEG2-CO₂H (6.9 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-56 was obtained as yellow solid in TFA salt form (8.7 mg, 61%). ¹H NMR (800 MHz, CD₃OD) δ 8.28 (d, J=8.4 Hz, 1H), 8.02 (dd, J=10.4, 6.3 Hz, 2H), 7.93 (s, 1H), 7.88 (d, J=7.81 Hz, 1H), 7.78 (dd, J=26.3, 7.8 Hz, 3H), 7.70 (d, J=8.0 Hz, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 6.98-6.92 (m, 2H), 6.79 (t, J=6.8 Hz, 1H), 4.99 (dq,=11.7, 6.6, 5.3 Hz, 1H), 3.69 (t, J=5.9 Hz, 2H), 3.63 (t, J=5.2 Hz, 2H), 3.56 (s, 4H), 3.47 (t, J=7.4 Hz, 2H), 3.39 (t, J=5.2 Hz, 2H), 2.89 (dt, J=30.3, 6.5 Hz, 4H), 2.80 (ddd, J=18.3, 13,7, 5.21 Hz, 1H), 2.67 (dddt, J=53.5, 17.7, 13.2, 6.6 Hz, 4H), 2.42 (t, J=5.9 Hz, 2H), 2.36-2.30 (m, 1H), 2.09-2.01 (m, 2H). ESI-MS (m/z) [M+H]⁺: 891.3945.

Example 133 Synthesis of XF067-57

XF067-57 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-CH₂CH₂-PEG3-CO₂H (7.6 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-57 was obtained as yellow solid in TFA salt form (7.9 mg, 53%). ¹H NMR (800 MHz, CD₃OD) δ 8.29 (d, J=8.4 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 7.96 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.79 (dd, J=15.4, 7.7 Hz, 3H), 7.71 (d, J=8.0 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 6.98 (t, J=7.4 Hz, 2H), 6.80 (s, 1H), 5.01 (dd, J=12.9, 5.3 Hz, 1H), 3,67 (i,=6.0 Hz, 2H), 3.65 (t, J=5.2 Hz, 2H), 3.62 (s, 4H), 3.58 (t, J=4.5 Hz, 2H), 3.56-3.52 (m, 2H), 3.48 (t, J=7.5 Hz, 2H), 3.40 (t, J=5.2 Hz, 2H), 2.95-2.85 (m, 4H), 2.82 (ddd, J=18.2, 13.7, 5.3 Hz, 1H), 2.75-2.60 (m, 4H), 2.41 (t, J=5.9 Hz, 2H), 2.36-2.30 (m, 1H), 2.11-2.02 (m, 2H). ESI-MS (m/z) [M+H]⁺: 935.4178.

Example 134 Synthesis of XF067-58

XF067-58 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-CH₂CH₂-PEG4-CO₂H (8.3 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-58 was obtained as yellow solid in TFA salt form (8 mg, 51%). ¹H NMR (800 MHz, CD₃OD) d 8.28 (d, J=8.4 Hz, 1H), 8.04 (q, J=6.4, 4.3 Hz, 3H), 7.87 (dd, J=23.8, 7.7 Hz, 2H), 7.83 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.01 Hz, 2H), 7.44-7.34 (m, 2H), 7.28 (d, J=7.5 11z, 1H), 7.00-6.94 (m, 1H), 6.83 (dd, J=19.1, ⁷. 7 Hz, 2H), 5.01 (dd, J=12.9, 5.4 Hz, 1H), 3.72-3.69 (m, 2H), 3.67-3.60 (m, 6H), 3.62-3.56 (m, 6H), 3.58-3.53 (m, 2H), 3.49 (t, J=7.7 Hz, 2H), 3.28 (dq, J=8.6, 5.1, 4.5 Hz, 2H), 2.92 (dt, J=16.0, 7.7 Hz, 2H), 2.89-2.79 (m, 3H), 2.79-2.63 (m, 4H), 2.45 (t, J=5.8 Hz, 2H), 2.35 (qd, J=10.1, 5.0 Hz, 1H), 2.07 (d, J=14.0 fIz, 2H). EST-MS (m/z) [M+H]⁺: 979.4459.

Example 135 Synthesis of XF067-59

XF067-59 was synthesized following the standard procedure for preparing XF067-31 from intermediate 9 (9.3 mg, 0.016 mmol), PML-CH₂CH₂-PEGS-CO₂H (9 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-59 was obtained as yellow solid in TFA salt form (7.8 mg, 48%). NMR (800 MHz, CD₃OD) δ 8.30 (d, J=8.3 Hz, 1H), 8.09-7.98 (m, 3H), 7.90 (d, J=7.8 Hz, 1H), 7.84 (dd, J=14.9, 7.9 Hz, 3H), 7.72 (d, J=8.1 Hz, 2H), ⁷. 50 (t, J=7.8 Hz, 1H), 7.41-7.35 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.02 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.84 (s, 1H), 5.02 (dd, J=12.8, 5.2 Hz, 1H), 3.70 (q, J=5.6 Hz, 2H), 3.62-3.55 (m, 14H), 3.55-3.46 (m, 6H), 3.38-3.34 (m, 2H). 2.97-2.86 (m, 4H), 2.83 (ddd, J=18.2, 13.8, 5.6 Hz, 1H), 2.78-2.72 (m, 2H), 2.71 (s, 1H), 2.70-2.63 (m, 1H), 2.44 (t, J=5.8 Hz, 2H), 2.37-2.32 (m, 1H), 2.12-2.03 (m, 2H). ESI-MS (m/z) [M+H]⁺: 1023.4716.

Example 136 Synthesis of Intermediate 13

The intermediate 10 was synthesized following a known procedure (Heerding et al., 2008). To the suspension of intermediate 10 (119 mg×3, 0.5 mmol) and methyl-4-oxobutanonate (58 mg×3, 0.5 mmol) in 5 mL of DCM was added sodium triacetoxyborohydride (211 mg×3, 1.0 mmol) in three times. Once the reaction mixture became clear solution, saturated NaHCO₃ solution was added to quench the reaction. After the organic phase was separated, the aqueous phase was extracted with DCM (10 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The resulting residue was dissolved in DCM (15 mL). To the resulting solution were added di-tert-butyl decarbonate (272 mg, 1.25 mmol) and triethylamine (188 mg, 1.86 mmol). The reaction was stirred for 30 min, before the reaction mixture was concentrated. The resulting residue was purified by silica gel column (Hexane/EA=1:3) to afford intermediate 11 as yellow solid (178 mg, 53%). ESI m/z 548.8 [M+H]⁺. Intermediate 11 (178 mg, 0.34 mmol) was dissolved in DMSO (5 mL) in a pressure vessel. To the resulting solution were added 2-methylbut-3-yn-2-ol (371 μL, 4.1 mmol), zinc powder (68 mg, 1.02 mmol), NaI (16 mg, 0.11 mmol), DBU (153 μL, 1.02 mmol), and triethylamine (207 μL, 1.02 mmol). The reaction was degassed for 5 min, before the catalyst Pd(PPh₃)₄ (40 mg, 10 mol %) was added. The reaction vessel was purged with nitrogen, sealed and heated to 80° C. for 1 h. The reaction was quenched by pouring into saturated NH₄Cl. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the intermediate 12, which was used in the next step without further purification. The intermediate 12 (146 mg, 0.25 mmol) was dissolved in methanol (5 mL). To the resulting solution was added NaOH (0.5 inL, 3 N). The reaction was heated to 60° C., for 1 h, before the reaction mixture was concentrated. The resulting residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford Intermediate 13 as white solid in TFA salt form (128.3 mg, 90%). 1H NMR (500 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.03 (s, 2H), 4.93-4.74 (m, 2H), 4.40-4.26 (m, 2H), 3.39 (t, J=7.1 Hz, 2H), 3.22 (t, J=7.2 Hz, 2H), 2.21 (t, J=7.2 11z, 2H), 2.13-2.02 (m, 2H), 1.82-1.69 (m, 2H) 1.47 (t, J=7.0 Hz, 3H), 1.41-1.30 (m, 15H). ESI-MS (m/z) [M+H]⁺: 572.3213

Example 137 Synthesis of XF067-84

To a solution of Intermediate 13 (9.1 mg, 0.016 mmol) in DMSO (1 mL) were added VHL-CH₂-PEG1-NH₂ (9.1 mg, 0.016 mmol, 1.0 equiv), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (1-hydroxy-7-azabenzo-triazole) (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (N-Methylmorpholine) (4.8 mg, 0.048mmol, 3.0 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford the corresponding product. After this product was dissolved in DCM (1mL), the reaction mix are was treated with TFA (1 mL) for 30 min. After the solvent was evaporated, the residue was purified by preparative HPLC (10%-100% methanol/0.1% TFA in H₂O) to afford XF067-84 as white solid in TFA salt form (6.1 mg, 39%), ¹H NMR (500 MHz, CD₃₀D) 6 8.97 (d, J=5.7 Hz, 1H), 8.23 (s, 1H), 7.51-7.34 (m, 4H), 5.05 (q, J=7.0 Hz, 2H), 4.74-4.65 (m, 1H), 4.64-4.28 (m, 6H), 4.13-3.93 (m, 2H), 3.93-3.77 (m, 2H), 3.68-3.49 (m, 2H), 3.43-3.35 (m, 4H), 3.24-3.07 (m, 2H), 2.58-2.33 (m, 714), 2.27 (dd, J=13.2, 7.6 Hz, 1H), 2.10 (ddd, J=13.5, 9.4, 4.4 Hz, 1H), 2.00 (h, J=7.2 Hz, 2H), 1.69 (s, 6H), 1.58 (t, J=7.0 Hz, 3H), 1.05 (s, 9H). ESI-MS (m/z) [M+H]⁺: 985.4728.

Example 138 Synthesis of XF067-85

XF067-85 was synthesized follow the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-CH₂CH₂-PEG1-NH₂ (12.4 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-85 was obtained as white solid in TFA salt form (11.8 mg, 74%). NMR (500 MHz, CD₃OD) δ 897 (s, 1H), 8.24 (s, 1H), 7.55-7.32 (m, 4H), 5.05 (q, J=7.1 Hz, 2H), 4.71-4.63 (m, 1H), 4.64-4.48 (m, 5H), 4.41 (d, J=15.4 Hz, 1H), 3.96-3.80 (m, 2H), 3.71 (tt, J=10.5, 4.8 Hz, 2H), 3.50 (t, J=5.4 Hz, 2H), 3.38-3.33 (m, 4H), 3.16 (t, J=7.0 Hz, 2H), 2.56-2.36 (m, 9H), 2.26 (ddt, J=13.2, 7.7, 1.9 Hz, 1H), 2.10 (ddd, J=13.3, 9.2, 4.4 Hz, 1H), 1.98 (p, J=6.8 Hz, 2H), 1.69 (s, 611), 1.58 (t, J=7.1 Hz, 3H), 1.05 (s, 9H). ESI-MS (m/z) [M+H]⁺: 999.4875.

Example 139 Synthesis of XF067-86

XF067-86 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-CH₂-PEG2-NH₂ (9.8 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-86 was obtained as white solid in TFA salt form (10.6 mg, 64%). ¹H NMR (500 MHz, CD₃OD) δ 9.01 (d, J=2.9 Hz, 1H), 8.26 (d, J=3.0 Hz, 1H), 7.53-7.44 (m, 4H), 5.06 (q, J=7.0 Hz, 2H), 4.95-4.71 (m, 1H), 4,64-4.31 (m, 6H), 4.03-4.01 (m, 2H), 3.94-3.78 (m, 2H), 3.80-3.58 On, 4H), 3.56-3.48 (m, 2H), 3.46-3.26 (m, 4H), 3.22-3.08 (m, 2H), 2.59-2.35 (n, 7H), 2.36-2.23 (m, 1H), 2.19-2.06 (m, 1H), 2.03-1.93 (m, 2H), 1.70 (s, 6H), 1.59 (t, J-7.0 Hz, 1.06 (s, 9H). ESI-MS (m/z) [M+H]⁺1029.4983.

Example 140 Synthesis of XF067-87

XF067-87 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-CH₂CH₂-PEG2-NH₂ (13.1 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 triL). XF067-87 was obtained as white solid in TFA salt form (6.4 mg, 38%). ¹H NMR (500 MHz, CD₃OD) δ 9.01 (s, 1H), 8.26 (s, 1H). 7.54-7.36 (m, 4H), 5.07 (q, J=7.1 Hz, 2H), 4.67 (d, J=6.2 Hz, 1H), 4.64-4.47 (m, 5H), 4.39 (d, J=15.4 Hz, 1H), 3.91 (d, J=11.0 Hz, 1H), 3.82 (dd, J=11.0, 3.9 Hz, 1H), 3.80-3.69 (n, 2H), 3.66-3.56 (m, 4H), 3.50 (t, J=5.4 Hz, 2H), 3.36-3.31 (m, 4H), 3.17 (t, J=7.0 Hz, 2H), 2.59 (ddd., J=15.0, 7.3, 5.2 Hz, 1H), 2.55-2.34 (m, 8H), 2.24 (ddt, J=13.3, 7.6, 2.0 Hz, 1H), 2.10 (ddd, J=13.3, 9.1, 4.5 Hz, 1H), 1.99 (p, J=6.9 Hz, 2H), 1.70 (s, 6H), 1.59 (t, J=7.1 Hz, 3H), 1.05 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1043.5145.

Example 141 Synthesis of XF067-88

XF067-88 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-CH₂-PEG3-NH₂ (13.5 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 tng, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-88 was obtained as white solid in TFA salt form (8.1 mg, 47%). ¹H NMR (500 MHz, CD₃OD) δ 9.00 (s, 1+1), 8.25 (s, 1H), 7.49-7.41 (m, 4H), 5.06 (q, J=6.9 Hz, 2H), 4.75-4.64 (m, 1H), 4.64-4.45 (m, 5H), 4.48-4.30 (m, 1H), 4.15-3.97 (n, 2H), 3.93-3.78 (m, 2H), 3.78-3.57 (n, 8H), 3.49 (t, J=5.4 Hz, 2H), 3.34-3.24 (m, 4H), 3.17 (d, J=7.1, 2.4 Hz, 2H), 2.54-2.33 (m, 7H), 2.33-2.21 (m, 1H), 2.17-2.05 (n, 1H), 2.04-1.92 (m, 2H), 1.75-1.63 (n, 6H), 1.59 (tJ=7.1 Hz, 3H), 1.06 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1073.5231.

Example 142 Synthesis of XF067-89

XF067-89 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-CH₂CH₂-PEG3-NH₂ (13.8 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-89 was obtained as white solid in TFA salt form (10.7 mg, 61%). ¹H NMR (500 MHz, CD₃OD) δ 9.02 (s, 1H), 8.27 (s, 1H), 7.59-7.33 (m, 4H), 5.07 (q, J=7.2 Hz, 2I-I), 4.73-4.62 (m, 1H), 4.62-4.47 (m, 5H), 439 (dd, J=15.6, 2.61 Hz, 1H), 3.94-3.87 (m, 1H), 3.87-3.66 (m, 3H), 3.70-3.54 (m, 8H), 3.50 (t, J=5.4 Hz, 2H), 3.37-3.30 (m, 4H), 3.17 (t, J=7.0 Hz, 2H), 2.60 (ddd, J=15.0, 7.5, 5.2 Hz, 1H), 2.52-2.30 (m, 8H), 2.24 (ddt, J=13.3, 7.7, 2.1 Hz, 1H), 2.10 (ddd, J=13.3, 9.2, 4.4 Hz, 1H), 2.00 (p, J=6.8 Hz, 2H), 1.70 (s, 6H), 1.60 (t, J=7.1 Hz, 3H), 1.06 (s, 9H). ESI-MS [M+H]⁺: 1087.5383.

Example 143 Synthesis of XF067-90

XF067-90 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-CH₂CH₂-PEG4—NH2 (11.4 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and

NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 triL). XF067-90 was obtained as white solid in TFA salt form (12.6 mg, 70%). ¹H NMR (500 MHz, CD₃₀D) 6 9.02 (s, 1H), 8.27 (s, 1H), 7.56-7.33 (m, 4H), 5.07 (q, J=7.1 Hz, 2H), 4.65 (s, 1H), 4.62-4.46 (m, 5H), 4.38 (d, J=15.5 Hz, 1H), 3.90 (d, J=11.0 Hz, 1H), 3.82 (dd, J=11.0, 3.9 Hz, 1H), 3.74 (dq, J=9.7, 4.8, 4.2 Hz, 2H), 3.67-3.55 (m, 12H), 3.51 (t, Jβ5.4 Hz, 2H), 3.40-3.32 (m, 4H), 3.17 (t, J=7.1 Hz, 2H), 2.60 (ddd, J=15.0, 7.3, 5.3 Hz, 1H), 2.55-2.29 (m, 8H), 2.24 (ddt, J=13.2, 7.7. 2.0 Hz, 1H), 2.10 (ddd, J=13.3, 9.1, 4.5 Hz, 1H), 2.00 (td, J=13.7, 12.3, 5.5 Hz, 2H), 1.70 (s, 6H), 1.60 (t, J=7.1 Hz, 3H), 1.05 (s, 9H). ESI-MS (m/z) for [M+H]⁺: 1131.5653.

Example 144 Synthesis of XF067-91

XF067-91 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-CH₂CH₂-PEGS-NH₂ (15.2 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-91 was obtained as white solid in TFA salt form (9.4 mg, 50%) ¹H NMR (500 MHz, CD₃OD) δ 8.99 (s, 1H), 8.25 (s, 1H), 7.53-7.36 (m, 4H), 5.07 (q, J=7.1 Hz, 2H), 4.66 (s, 1H), 4.61-4.47 (m, 5H), 4.38 (d, J=15.5 Hz, 1H), 3.90 (d, J=11.1 Hz, 1H), 3.86-3.70 (m, 3H), 3.66-3.56 (m, 16H), 3.50 (t, J=5.4 Hz, 2H), 3.36-3.28 (m, 414), 3.18 (t, J=7.0 Hz, 2H), 2.60 (ddd, J=14.8, 7.4, 5.1 Hz, 1H), 2.52-2.32 (m, 8H), 2.24 (ddt, J=11.7, 7.7, 1.9 Hz, 1H), 2.15-2.02 (m, 1H), 1.99 (q, J=6.8 Hz, 2H), 1.69 (s, 6H), 1.59 (t, J=7.1 Hz, 3H), 1.06 (s, 9H). ESI-MS (m/z) for [M+H]⁺: 1175.5911.

Example 145 Synthesis of XF067-92

XF067-92 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), NIFIL-C₁—NH2 (11.4 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (I mL). XF067-92 was obtained as white solid in TFA salt form (9.3 mg, 62%). ¹H NMR (500 MHz, CD₃OD) δ 9.01 (d, J=6.5 Hz, 1H), 8.25 (d, J=6.2 Hz, 1H), 7.56 7.39 (m, 4H), 5.06 (dd, J=12.7, 5.7 Hz, 2H), 4.83-4.31 (m, 7H), 4.08-3.78 (m, 4H), 3.46-3.35 (m, 2H), 3.21 (q, J=7.2, 5.9 Hz, 2H), 2.80-2.29 (m, 7H), 2.33-2.18 (m, 1H), 2.18-1.90 (m, 3H), 1.70 (s, 6H), 1.64-1.51 (m, 3H), 1.06 (d, J=10.6 Hz, 9H). ESI-MS (m/z) for [M+H]⁺: 941.4458.

Example 146 Synthesis of XF067-93

XF067-93 was synthesized following the standard procedure for preparing XF067-4 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-C2-NH₂ (11.7 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv) HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-93 was obtained as white solid in TFA salt form (12.9 mg, 84%). ¹H NMR (500 MHz, CD₃OD) δ 9.02 (s, 1H), 8.26 (s, 1H), 7.51-7.28 (m, 4H), 5.07 (q, J=7.0 Hz, 2H), 4.62 (s, 1H), 4.59-4.47 (m, 5E1), 4.40 (d, J=15.5 Hz, 1H), 3.95 (d, J=11.0 Hz, 1H), 3.82 (dd, J=11.0, 3.9 Hz, 1H), 3.47-3.33 (m, 4H), 3.17 (t, J=7.2 Hz, 2H), 2.57-2.33 (m, 9H), 2.26 (dd, J=13.3, 7.6 Hz, 1H), 2.11 (ddd, J=13.4, 9.3, 4.3 Hz, 1H), 1.99 (p, J=6.8 Hz, 2H), 1.70 (s, 6H), 1.60 (t, J=7.1 Hz, 3H), 1.05 (s, 9H). ESI-MS (m/z) [M+H]⁺: 955.4613.

Example 147 Synthesis of XF067-94

XF067-94 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-C3—NIH (11.9 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-94 was obtained as white solid in TFA salt form (9.3 mg, 60%). ¹H NMR (500 MHz, CD₃OD) δ 9.02 (s, 1H), 8.27 (s, 1H), 7.58 7.34 (m, 414), 5.07 (q, J=7.3, 6.3 Hz, 2H), 4.75-4.48 (m, 611), 4.40 (dd, J=15.5, 4.9 Hz, 1H), 3.96-3.77 (m, 2H), 3,40-3.32 (m, 4H), 3.18 (q, J=7.2, 6.4 Hz, 2H), 2.63-2.19 (m, 10H), 2.11 (ddd, J=13.3, 9.2, 4.6 Hz, 1H), 2.00 (p, J=6.6 Hz, 2H), 1.85-1.64 (m, 8H), 1.60 (t, J=7.0 Hz, 3H), 1.06 (d, J=4.6 Hz, 9H). ESI-MS (m/z) for [M+H]⁺: 969.4754.

Example 148 Synthesis of XF067-95

XF067-95 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-C4-NH₂ (9.1 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 nth). XF067-95 was obtained as white solid in TFA salt form (6.7 mg, 43%), ¹H NMR (500 MHz, CD₃OD) δ 8.98 (s, 1H), 8.24 (s, 1H), 7.52-7.37 (m, 4H), 5.06 (q, J=7.1 Hz, 2H), 4.63 (s, 1H), 4.55 (ddt, J=17.1, 103, 6.2 Hz, 5H), 4.39 (d, J=15.4 Hz, 1H), 3.91 (d, J=11.0 Hz, 1H), 3.82 (dd, J=11.0, 4.0 Hz, 1H), 3.41-3.26 (m, 2H), 3.22-3.04 (m, 4H), 2.51-2.35 (m, 7H), 2.35-2.18 (m, 3H), 2.17-2.05 (m, 1H), 1.99(p, J=6.9 Hz, 2H), 1.69 (s, 6H), 1.65-1.40 (m, 71-1), 1.04 (s, 9H). ESI-MS (m/z) [M+H]⁺: 983.4927.

Example 149 Synthesis of XF067-96

XF067-96 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-C5-NH₂ (9.3 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-96 was obtained as white solid in TFA salt form (6.7 mg, 42%). ¹H NMR (500 MHz, CD₃OD) δ 8.97 (s, 1H), 8.23 (s, 1H), 7.54-7.35 (m, 4H), 5.06 (q, J=7.0 Hz, 2H), 4.64 (s, 1H), 4.61-4.47 (m, 5H), 4.38 (d, J=15.5 Hz, 1H), 3.92 (d, J=11.0 Hz, 1H), 3.83 (dd, J=10.9, 3.9 Hz, 1H), 3.39-3.32 (m, 2H), 3.17 (t, J=7.0 Hz, 2H), 3.08 (t, J=7.1 Hz, 2H), 2.50 (s, 3H), 2.48-2.35 (m, 4H), 2.34-2.20 (m, 3H), 2.11 (ddd, J=13.3, 9.1, 4.5 Hz, 1H), 1.99 (p, J=6.9 Hz, 2H), 1.69 (s, 6H), 1.65-1.54 (m, 5H), 1.48 (p, J=7.3 Hz, 2H), 1.39-1.25 (m, 2H), 1.05 (s, 9H). ESI-MS (m/z) for [M+H]⁺: 997.5079.

Example 150 Synthesis of XF067-97

XF067-97 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-C6—NI-I2 (9.5 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol. 1.5 equiv). HOAt (3.3 mg, 0.024 mmol, 1.5 equiv). and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 XF067-97 was obtained as white solid in TFA salt form (13.9 mg, 86%). NMR (500 MHz, CD₃OD) δ 9.11-8.85 (m, 1H), 8.25 (s, 1H), 7.58-7.32 (m, 4H), 5.07 (tt, J=9.3, 4.8 Hz, 2H), 4.72-4.48 (m, 6H) 4.39 (dd, J=15.4, 3.3 Hz, 1H) 3.92 (d, J=10.7 Hz, 1H), 3.83 (d, J=10.9, 3.6 Hz, 1H), 3.33-3.27 (m, 2H), 3.22-3.14 (m, 2H), 3.11-2.95 (m, 2H), 2.57-2.17 (m, 10H), 2.11 (ddt, J=13.2, 8.9, 3.9 Hz, 1H), 2.00 (dtt, J=12.8, 8.9, 4.6 Hz, 2H), 1.73-1.51 (m, 9H), 1.51-1.41 (m, 2H), 1.41-1.23 (m, 1.05 (s, 9H). ESI-MS (m/z) for [M+H]⁺: 1011.5239.

Example 151 Synthesis of XF067-98

XF067-98 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-C7-NH₂ (12.8 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-98 was obtained as white solid in TFA salt form (8.6 mg, 52%). ¹H NMR (500 MHz, CD₃OD) d 8.97 (s, 1H), 8.22 (s, 1H), 7.57-7.19 (m, 4H), 5.14-4.97 (m, 2H), 4.67-4.43 (m, 6H), 4.38 (dd, J=15.5, 2.6 Hz, 1H), 3.92 (d, J=11.0 Hz, 1H), 3.82 (dd, J=11.0, 3.9 Hz, 1H), 3.32 (d, J=2.2 Hz, 2H), 3.17 (td, J=7.0, 2.6 Hz, 2H), 3.06 (td, J=7.1, 2.6 Hz, 2H), 2.54-2.35 (m, 8H), 2.34-2.18 (m, 2H), 2.13-2.06 (m, 1H), 2.04-1.93 (m, 2H), 1.77-1.52 (m, 9H), 1.44 (p, J=7.2 Hz, 2H), 1.39-1.12 (m, 8H), 1.05 (s, 9H), ESI-MS (m/z) [M+H]⁺: 1025.5387.

Example 152 Synthesis of XF067-99

XF067-99 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), V1-IL-C₈—NI-I₂ (10 Ing 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-99 was obtained as white solid in TFA salt form (7 mg, 42%). ¹H NMR (500 MHz, CD₃OD) δ 8.95 (s, 1H), 8.21 (s, 1H), 7.54-7.31 (m, 4H), 5.06 (q, J=7.1 Hz, 2H), 4.65 (s, 1171), 4.62-4.48 (m, 5H), 4.38 (d, J=15.5 Hz, 1H), 3.92 (d, J=11.0 Hz, 1H), 3.83 (dd, J=11.0, 3.9 Hz, 1H), 3.37-3.29 (m, J=2.8 Hz, 2H), 3.17 (t, J=6.9 Hz, 2H), 3.05 (t, J=7.1 Hz, 2H), 2.52-2.37 (m, 7H), 2.34-2.19 (m, 3H), 2.15-2.04 (m, 1H), 1.98 (p, J=6.7 Hz, 2H), 1.69 (s, 6H), 1.65-1.54 (m, 3H), 1.43 (p, J=7.1 Hz, 2H), 1.30 (d, J=13.7 Hz, 1014), 1.05 (s, 914). ESI-MS (m/z) [M+H]⁺: 1039.5534.

Example 153 Synthesis of XF067-100

XF067-100 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VFL-C9-NH₂ (13.2 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL), XF067-100 was obtained as white solid in TFA salt form (3.9 mg, 23%). ¹H NMR (500 MHz, CD OD) δ 8.92 (d, J=4.5 Hz, 1H), 8.17 (d, J=5.8 Hz, 1H), 7.62-7.29 (m, 4H), 5.15-5.00 (m, 2H), 4.65 (d, J=2.5 Hz, 1H), 4.63-4.46 (m, 5H), 4.42-4.29 (m, 1H), 3.92 (d, J=11.0 Hz, 1H), 3.83 (dd, J=11.0, 3.9 Hz, 1H), 3.35-3.29 (m, 2H), 3.17 (dd, .I=7.8, 5.9 Hz, 2H), 3.05 (td, J=7.3, 3.5 Hz, 2H), 2.58-2.18 (m, 10H), 2.11 (ddd, J=13.2, 9.0, 4.5 Hz, 1H), 2.04-1.89 (m, 2H), 1.76-1.50 (m, 9H), 1.42 (t, J=7.0 Hz, 2H), 1.38-1.12 (m, 12H), 1.05 (s, 9H). ESI-MS (m/z) [M+H]^(P): 1053.5711.

Example 154 Synthesis of XF067-101

XF067-101 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), VHL-C10—NH2 (10.4 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-101 was obtained as white solid in TFA salt form (4.8 mg, 26%). ¹H NMR (500 MHz, CD₃OD) δ 8.96 (d, J=2.6 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H), 7.58-7.32 (m, 4H), 5.13-5.00 (m, 2H), 4.65 (s, 1H), 4.63-4.50 (m, 5H), 4.37 (dd, J=15.4, 2.8 Hz, 1H), 3.92 (d, J=11.0 Hz, 1H), 3.83 (dd, J=11.0, 3.9 Hz, 1H), 3.33-3.30 (m, 2H), 3.21-3.14 (m, 2H), 3.06 (dd, J=9.4, 4.5 Hz, 2H), 2.54-2.38 (m, 7H), 136-120 (m, 3H), 2.11 (ddd, J=13.3, 9.1, 4.5 Hz, 1H), 2.06-1.91 (m, 2H), 1.75-1.57 (m, 9H), 1.43 (t, J=7.1 Hz, 2H), 1.39-1.22 (m, 14H), 1.05 (s, 9H). ESI-MS (m/z) [M+H]⁺: 1067.5853.

Example 155 Synthesis of XF067-102

XF067-102 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-CH₂CH₂-PEGI-NII₂ (7.6 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-102 was obtained as yellow solid in TFA salt form (9.6 mg, 26%). ¹H NMR (500 MHz, CD₃OD) δ 8.17 (s, 1H), 7.50 (dd, J=8.6, 7.1 Hz, 1H), 7.01 (t, J=8.2 Hz, 2H), 5.06 (dd, J=12.7, 5.5 Hz, 1H), 4.99 (q, J=7.1 Hz, 2H), 4.50 (t, J=5.8 Hz, 2H), 3.66 (t, J=5.1 Hz, 2H), 3.52 (t, J=5.3 Hz, 2H), 3.44 (t, J=5.1 Hz, 2H), 3.40-3.26 (m, 4H), 3.14 (t, J=6.8 Hz, 2H), 2.88 (ddd, J=17.3, 13.8, 5.3 Hz, 1H), 2.81-2.63 (m, 2H), 2.48 (t, J=6.4 Hz, 2H), 2.39-2.35 (m, 2H), 2.13 (dtd, J=13.2, 5.3, 2.5 Hz, 1H), 1.97 (p, J=6.7 Hz, 2H), 1.69 (s, 6H), 1.53 (t, J=7.1 Hz, 3H). EST-MS (m/z) [M+H]⁺: 814.3611.

Example 156 Synthesis of XF067-103

XF067-103 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-CH₂CH₂-PEG2—NH2 (8.3 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mt.). XF067-103 was obtained as yellow solid in TFA salt form (7.8 mg 57%). ¹H NMR (500 MHz, CD₃OD) δ 8.16 (s, 1H), 7.53 (dd, J=8.5, 7.1 Hz, 1H), 7.05 (dd, J=15.6, 7.8 Hz, 2H), 5.09-4.97 (m, 3H), 4.51 (t, J=5.9 Hz, 2H), 3.73 (1.1=5.2 Hz, 2H), 3.70-3.60 (m, 4H), 3.55-3.46 (m, 4H), 3.34-3,24 (m, 4H), 3.14 (1.1=7.0 Hz, 2H), 2.87 (ddd, J=17.6, 14.0, 5.3 Hz, 1H). 2.80-2.64 (m, 2H), 2.46-2.34 (m, 4H), 2.13 (dtd, J=13.1, 5.7, 2.9 Hz, 1H), 1.97 (p, J=6.8 Hz, 2H), 1.69 (s, 6H), 1.56 (t, J=7.1 Hz, 3H). ESI-MS (m/z) [M+H]⁺: 858.3879.

Example 157 Synthesis of XF067-104

XF067-104 was synthesized following the standard procedure for preparing XF067-4 from intermediate 13 (9.1 mg, 0.016 mmol), PML-CH₂CH₂-PEG3-NH₂ (9 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mt.). XF067-104 was obtained as yellow solid in TFA salt form (11.3 mg, 78%). ¹H NMR (500 MHz, CD₃OD) δ 8.23 (s, 1H), 7.51 (dd, J=8.6, 7.1 Hz, 1H), 7.02 (dd, J=19.2, 7.8 Hz, 2H), 5.0-4.99 (m, 3H), 4.52 (t, J=5.9 Hz, 2H), 3.73 (t, J=5.2 Hz, 2H), 3.68 (s, 4H), 3.69-3.63 (m, 2H), 3.66-3.55 (m, 2H), 3.49 (dt, J=7.7, 5.3 Hz, 4H), 3.37-3.25 (m, 4H), 3.15 (t, J=7.0 Hz, 2H), 2.88 (ddd, J=17.6, 14.0, 5.3 Hz, 1H), 2.82-2.65 (m, 2H), 2.47-2.38 (m, 4H), 2.13 (dtd, J=13.1, 5.7, 2.9 Hz, 1H), 1.98 (p, J=6.9 Hz, 2H), 1.70 (s, 6H), 1.57 (t, J=7.1 Hz, 3H). ESI-MS (m/z) [M+H]⁺: 902.4134.

Example 158 Synthesis of XF067-105

XF067-105 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-CH₂CH₂-PEG4-NH₂ (9 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-105 was obtained as yellow solid in TFA salt form (5.2 mg, 34%), 41 NMR (500 MHz, CD₃OD) δ 8.19 (s, 1H), 7.52 (dd, J=8.6, 7.1 Hz, 1H), 7.04 (dd, J=19.6, 7.8 Hz, 2H), 5.09-4.98 (m, 3H), 4.51 (t, J=5.8 Hz, 2H), 3.73 (t, J=5.2 Hz, 2H), 3.70-3.60 (m, 10H), 3.58 (dd, J=6.1, 3.4 Hz, 2H), 3.49 (t, J=5.3 Hz, 4H), 3.34-3.25 (m, 4H), 3.16 (t, J=7.0 Hz, 2H), 2.88 (ddd, J=17.5, 14.0, 5.3 Hz, 1H), 2.81-2.65 (m, 2H), 2.46 (t, J=6.5 Hz, 2H), 2.41-2.37 (m, 2H), 2.17-2.10 (m, 1H), 1.98 (p, J=6.9 Hz, 2H), 1.69 (s, 6H), 1.57 (t, J=7.1 Hz, 3H). ESI-MS (m/z) [M+H]⁺: 946.4412.

Example 159 Synthesis of XF067-106

XF067-106 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-CH₂CH₂-PEG5-NH₂ (9.6 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-106 was obtained as yellow solid in TFA salt form (12.8 mg, 81%). ¹H NMR (500 MHz, CD₃OD) δ 8.24 (d, J=3.6 Hz, 1H), 7.60-7.45 (m, 1H), 7.04 (ddd, J=19.7, 8.0, 3.7 Hz, 2H), 5.05 (td, J=8.7, 7.4, 3.81 Hz, 3H), 4.54 (q, J=5.8, 5.0 Hz, 2H), 3.82-3.56 (m, 18H), 3.49 (q, J=5.3 Hz, 4H), 3.37-3.27 (m, 4H), 3.23-3.15 (m, 2H), 2.93-2.82 (m, 1H), 2.83-2.72 (m, 2H), 2.47-2.37 (m, 4H), 2.13 (dtd, J=13.0, 5.7, 2.9 Hz, 1H), 1.99 (p, J=6.8, 5.6 Hz, 2H), 1.70 (d, J=3.7 Hz, 6H), 1.62-1.53 (m, 3H). ESI-MS (nt/z) [M+H]⁺: 990.4668.

Example 160 Synthesis of XF067-107

XF067-107 was synthesized following the standard procedure for preparing XE067-4 from intermediate 13 (9.1 mg, 0.016 mmol), PML-C₂-NH₂ (7 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-107 was obtained as yellow solid in TFA salt form (12.1 mg, 98%). ¹H NMR (500 MHz, CD₃OD) δ 8.26 (d, J=13.2 Hz, 1H), 7.55-7.44 (m, 1H), 7.02 (dd, J=14.2, 7.8 Hz, 2H), 5.09-4.98 (m, 3H), 4.62-4.51 (m, 2H), 3.36-3.32 (m, 614), 3.15 (t, J=6.6 Hz, 2H), 2.87 (ddd, J=17.2, 13.8, 5.3 Hz, 1H), 2.81-2.62 (m, 2H), 2.51-2.43 (m, 2H). 2.39 (tq, J=12.7, 6.8 Hz, 2H). 2.13 (dtd., J=13.2, 5.4, 2.6 Hz, 1H), 2.01-1.94 (m, 2H), 1.69 (s, 6H), 1.64-1.52 (m, 3H).). ESI-MS (m/z) [M+H]⁺: 770.3356.

Example 161 Synthesis of XF067-108

XF067-108 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-C3-NH₂ (7.1 mg, 0.016 minol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv) HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-108 was obtained as yellow solid in TFA salt form (11.7 mg, 93%). ¹H NMR (500 MHz, CD₃OD) δ 8.25 (s, 1H), 7.51 (dd, J=8.6, 7.1 Hz, 1H) 6.99 (dd, J=7.8, 4.6 Hz, 2H), 5.08-4.98 (m, 3H), 4.54 (t, J=5.8 Hz, 2H), 3.39-3.29 (m, 4H), 3.31-3.22 (m, 2H), 3.18 (t, J=6.6 Hz, 2H), 2.87 (ddd, J=17.5, 14.0, 5.4 Hz, 1H), 2.80-2.64 (m, 2H), 2.51 (t, 6.4 Hz, 2H), 2.45-2.38 (m, 2.12 (ddt, J=13.1, 5.4, 2.8 Hz, 1H), 2.00 (q, J=6.5 Hz, 2H), 1.77 (q, J=6.4 Hz, 2H), 1.70 (s, 6H), 1.56 (t, J=7.1 Hz, 3H). ESI-MS (m/z) [M+H]⁺: 784.3534.

Example 162 Synthesis of XF067-109

XF067-109 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-C₄—NH2 (7.3 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-109 was obtained as yellow solid in TFA salt form (9.6 mg, 75%). 1H NMR (500 MHz, CD₃OD) δ 8.25 (s, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.03-6.96 (m, 2H), 5.04 (q, J=7.1, 6.3 Hz, 3H), 4.54 (t, J=5.8 Hz, 2H), 3.47-3.01 (m, 8H), 2.93-2.62 (m, 3H), 2.59-2.31 (m, 4H), 2.18-2.07 (m, 1H), 1.99 (p, J=6.4 Hz, 2H), 1.82-1.45 (m, 3H). ESI-MS (m/z) [M+H]⁺: 798.3667.

Example 163 Synthesis of XF067-110

XF067-110 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-C5-NH₂ (7.6 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-110 was obtained as yellow solid in TFA salt form (10.6 mg, 82%). ¹H NMR (500 MHz, CD₃OD) δ 8.18 (5, 1H) 7.49 (dd, J=8.5, 7.1 Hz, 1H), 6.98 (dd, J=7.8, 6.4 Hz, 2H), 5.08-4.96 (m, 3H), 4.51 (t, J=5.8 Hz, 2H), 3.34-3.23 (m, 3H), 3.20-3.07 (m, 4H), 2.88 (ddd, J=17.0, 13.7, 5.2 Hz, 1H), 2.81-2.64 (m, 2H), 2.47 (t, J=6.5 Hz, 2H), 2.39 (p, J=6.4 Hz, 2H), 2.08 (m, 1H), 1.98 (p, J=6.7 Hz, 2H), 1.69 (s, 6H), 1.69-1.60 (m, 2H), 1.58-1.47 (m, 5H), 1.40 (qd, J=8.5, 5.6 Hz, 2H). ESI-MS (m/z) [M+H]⁺: 812.3854.

Example 164 Synthesis of XF067-111

XF067-111 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-C₆—NH2 (6.5 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL), XF067-111 was obtained as yellow solid in TFA salt form (11.9 mg, 90%). ¹H NMR (500 MHz, CD₃OD) δ 8.24 (s, 1H), 7.60-7.48 (m, 1H), 7.15-6.86 (m, 2H), 5.04 (dt, J=12.3, 5.2 Hz, 3H), 4.54 (q, J=5.8, 4.9 Hz, 2H), 3.14 (dt, J=25.1, 7.0 Hz, 8H), 2.98 2.67 (m, 3H), 2.43 (dq, J=19.2, 7.8, 6.4 Hz, 4H), 2.19-2.10 (m, 1H), 1.99 (p, J=6.7 Hz, 2H), 1.83-1.15 (m, 17H). ESI-MS (m/z) [M+H]⁺: 826.3987.

Example 165 Synthesis of XF067-112

XF067-112 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-C₇-NH₂ (8 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-112 was obtained as yellow solid in TFA salt form (12.5 mg, 93%), ¹H NMR (500 MHz, CD₃OD) δ 8.22 (s, 1H), 7.53 (ddd, J=8.5, 7.2, 2.0 Hz, 1H), 7.01 (td, J=6.9, 2.2 Hz, 2H), 5.09-5.00 (m, 3H), 4.53 (t, J=5.9 Hz, 2H), 3.39-3.27 (m, 4H), 3.16 (t, J=6.9 Hz, 2H), 3.09 (t, J=7.1 Hz, 2H), 2.93-2.82 (m, 1H), 2.81-2.66 (m, 2H), 2.43 (dt, J=20.7, 6.9 Hz, 4H), 2.12 (dtd, J=13.0, 5.6, 2.8 Hz, 1H), 1.99 (p, J=6.9 Hz, 2H), 1.72-1.62 (m, 8H), 1.58 (t, J=7.1 Hz, 3H), 1.49-1.29 (m, 8H), ESI-MS (m/z) [M+H]⁺: 840.4157.

Example 166 Synthesis of XF067-113

XF067-113 was synthesized following the standard procedure for preparing XF067-84 from intermediate 13 (9.1 mg, 0.016 mmol), PML-C₈-NH₂ (8.2 mg, 0.016 mmol, 1.0 equiv), EDCI (4.6 mg, 0.024 mmol, 1.5 equiv), HOAt (3.3 mg, 0.024 mmol, 1.5 equiv), and NMM (4.8 mg, 0.048 mmol, 3.0 equiv) in DMSO (1 mL). XF067-113 was obtained as yellow solid in TFA salt form (12.6 mg, 98%). ¹H NMR (500 MHz, CD₃OD) δ 8.25 (d, J=2.8 Hz, 1H), 7.54 (ddd, J=8.5, 7.1, 2.3 Hz, 1H), 7.02 (dd, 7.8, 3.0 Hz, 2H), 5.10-5.01 (m, 3H), 4.54 (t, J=5.8 Hz, 2H), 3.34-3.27 (m, 4H), 3.17 (td, J=7.3, 2.6 Hz, 2H), 3.09-3.07 (m, 2H), 2.92-2.82 (m, 1H), 2.81-2.66 (m, 2H), 2.48-2.36 (m, 4H), 2.12 (dtd, J=13.1, 5.6, 2.8 Hz, 1H), 2.03-1.92 (m, 2H), 1.75-1.62 (m, 8H), 1.65-1.55 (m, 3H), 1.49-1.25 (m, 10H), ESI-MS (m/z) [M+H]⁺: 854.4313.

Compounds synthesized in the

Example s above are set forth in Table 1, below.

In Table 1, the left portion of the structure of the AKT disruptors/degraders binds to AKT (as, e.g., GSK690693 (Heading et al., 2008), GSK2110183 (Durable est al., 2014), GSK2141795 (Dumble et al., 2014), AZD5363 (Addie et al., 2013), GDC0068 (Blake et al., 2012), MK-2206 (Hirai et al., 2010), and ARQ-092 (Yu et al., 2015) do), and the right portion of the structure recruits the ubiquitination machinery to AKT, which induces poly-ubiquitination and degradation of AKT at the proteasome.

TABLE 1 Compound ID Structure Chemical Name XF038-157A

(2S,4R)-1-((2S,15S)-2-(tert- butyl)-15-(4-chlorophenyl)-16- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-4,10,16- trioxo-6-oxa-3,9,13- triazahexadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF038-158A

(2S,4R)-1-((2S,18S)-2-(tert- butyl)-18-(4-chlorophenyl)-19- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-4,13,19- trioxo-6,9-dioxa-3,12,16- triazanonadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF038-159A

(2S,4R)-1-((2S,25S)-2-(tert- butyl)-25-(4-chlorophenyl)-26- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-4,20,26- trioxo-7,10,13,16-tetraoxa- 3,19,23-triazahexacosanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF038-160A

(2S,4R)-1-((S)-2-(5-(3-(((S)-2- (4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)propanamido) pentanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF038-161A

(2S,4R)-1-((S)-2-(6-(3-(((S)-2- (4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)propanamido) hexanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF038-162A

(2S,4R)-1-((S)-2-(7-(3-(((S)-2- (4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-SH- cvclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)propanamido) heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF038-164A

(2S,4R)-1-((S)-2-(9-(3-(((S)-2- (4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)propanamido) nonanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF038-165A

(2S,4R)-1-((S)-2-(10-(3-(((S)-2- (4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)propanamido) decanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF038-166A

(2S,4R)-1-((S)-2-(11-(3-(((S)-2- (4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)propanamido) undecanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF042-162

(2S,4R)-1-((S)-2-(11-(3-(((S)-2- (4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)propanamido) undecanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-((S)-1-(4-(4-methylthiazol- 5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide XF042-171

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethyl) propanamide XF048-7

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(2-(2-(2- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl) propanamide XF048-8

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(2-(2-(2- (2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy) ethoxy)ethyl)propanamide XF038-176A

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(14-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12- tetraoxatetradecyl)propanamide XF038-177A

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(17-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15- pentaoxaheptadecyl) propanamide XF042-164

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethyl)propanamide XF042-165

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(3-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)propyl)propanamide XF042-166

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(4-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)butyl)propanamide XF042-167

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(5-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)pentyl)propanamide XF042-168

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(6-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)hexyl)propanamide XF048-5

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(7-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)heptyl)propanamide XF042-170

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(8-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)octyl)propanamide XF048-1

N-(2-(((N)-2-(4-chlorophenyl)- 3-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)ethyl)-3-(2- (2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy) propanamide XF048-2

N-(2-(((S)-2-(4-chlorophenyl)- 3-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)ethyl)-3-(2- (2-(2-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy) ethoxy)propanamide XF048-3

N-(2-(((S)-2-(4-chlorophenyl)- 3-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)ethyl)-1-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12-tetraoxapentadecan- 15-amide XF048-4

N-(2-(((S)-2-(4-chlorophenyl)- 3-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)ethyl)-1-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15- pentaoxaoetadecan-18-amide XF050-5

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(2-(2-(((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-2- oxoethoxy)acetyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-6

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(3-(3-(((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-3- oxopropoxy)propanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-7

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(2-(2-(2- (((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-2- oxoethoxy)ethoxy)acetyl) piperazin-1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-8

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(3-(2-(3- (((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-3- oxopropoxy)ethoxy)propanoyl) piperazin-1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-9

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-((S)-13- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine- 1-carbonyl)-14,14- dimethyl-11-oxo-3,6,9-trioxa- 12- azapentadecanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-10

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-((S)-15- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine- 1-carbonyl)-16,16- dimethyl-13-oxo-4,7,10-trioxa- 14- azaheptadecanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-11

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-((S)-18- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine- 1-carbonyl)-19,19- dimethyl-16-oxo-4,7,10,13- tetraoxa-17- azaicosanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-12

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-((S)-19- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine- 1-carbonyl)-20,20- dimethyl-17-oxo-3,6,9,12,15- pentaoxa-18- azahenicosanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-13

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-((S)-21- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine- 1-carbonyl)-22,22- dimethyl-19-oxo-4,7,10,13,16- pentaoxa-20- azatricosanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-14

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(4-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-4- oxobutanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-15

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(5-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-5- oxopentanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-16

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(6-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-6- oxohexanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-17

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(7-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-7- oxoheptanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-18

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(8-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-8- oxooctanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-19

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(9-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-9- oxononanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-20

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(10-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-10- oxodecanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-21

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(11-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-11- oxoundecanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-22

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)glycyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-23

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(3-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)propanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-24

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(4-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)butanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-25

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(5-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)pentanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-26

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(6-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)hexanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-27

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(7-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)heptanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-28

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(8-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)octanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-29

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(3-(2-((2- (2,6-dioxopipendin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)propanoyl) piperazin-1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF050-30

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(3-(2-(2- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy) propanoyl)piperazin-1- yl)propyl)-1- (7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperidine-4- carboxamide XF050-31

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(3-(2-(2-(2- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy) ethoxy)propanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-32

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12-tetraoxapentadecan- 15-oyl)piperazin-1-yl)propyl)- 1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-33

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15- pentaoxaoctadecan-18- oyl)piperazin-1-yl)propyl)-1- (7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperidine-4- carboxamide XF050-98

N¹-(2-(((S)-2-(4- chlorophenyl)-3-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7- dihydro-5H- cyclopenta[d]pynmidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)ethyl)-N¹²- ((S)-((2S,4R)-4-hydroxy-2- (((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2- yl)dodecanediamide XF050-132

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(8-((2- (2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4- yl)amino)octyl)propanamide XF050-133

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(8-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)oxy)octyl)propanamide XF050-134

N-(2-(((S)-2-(4-chlorophenyl)- 3-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)ethyl)-9-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)nonanamide XF056-93

3-(((S)-2-(4-chlorophenyl)-3- (4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)amino)-N-(9-(2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)nonyl)propanamide XF050-143

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(12-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-12- oxododecanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-144

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(13-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-13- oxotridecanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-145

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(14-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-14- oxotetradecanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF050-167

4-amino-N-((S)-1-(4- chlorophenyl)-3-(4-(11-(((S)-1- ((2S,4R)-4-hydroxy-2-(((S)-1- (4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-11- oxoundecanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF056-33

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15,18- hexaoxahenicosan-21- oyl)piperazin-1-yl)propyl)-1- (7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperidine-4- carboxamide XF056-34

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15,18,21,24- octaoxaheptacosan-27- oyl)piperazin-1-yl)propyl)-1- (7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperidine-4- carboxamide XF056-35

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15,18,21,24,27- nonaoxatriacontan-30- oyl)piperazin-1-yl)propyl)-1- (7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperidine-4- carboxamide XF056-36

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(1-((2-(2,6- dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)- 3,6,9,12,15- pentaoxaoctadecan-18- oyl)piperazin-1-yl)propyl)-1- (7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperidine-4- carboxamide XF056-37

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)- 3,6,9,12,15- pentaoxaoctadecan-18- oyl)piperazin-1-yl)propyl)-1- (7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperidine-4- carboxamide XF056-73

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(19-(2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)- 4,7,10,13,16- pentaoxanonadecanoyl)piperazin- 1-yl)propyl)-1-(7H- pyrrolo[2,3-d]pyrimidin-4- yl)piperidine-4-carboxamide XF061-10

4-amino-N-((1S)-1-(4- chlorophenyl)-3-(4-(11-(((S)-1- ((2R,4S)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-11- oxoundecanoyl)piperazin-1- yl)propyl)-1-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidine-4- carboxamide XF067-1

(2S,4R)-1-((S)-2-(2-(2-(3-(3-(3- (4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-2

(2S,4R)-1-((S)-2-(3-(2-(3-(3-(3- (4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-3

(2S,4R)-1-((S)-15-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,13- dioxo-6,9-dioxa-3,12- diazapentadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-4

(2S,4R)-1-((S)-16-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,14- dioxo-7,10-dioxa-3,13- diazahexadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-5

(2S,4R)-1-((S)-18-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,16- dioxo-6,9,12-trioxa-3,15- diazaoctadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-6

(2S,4R)-1-((S)-19-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,17- dioxo-7,10,13-trioxa-3,16- diazanonadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-7

(2S,4R)-1-((S)-22-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,20- dioxo-7,10,13,16-tetraoxa- 3,19-diazadocosanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-8

(2S,4R)-1-((S)-25-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,23- dioxo-7,10,13,16,19-pentaoxa- 3,22-diazapentacosanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-9

(2S,4R)-1-((S)-2-(2-(3-(3-(3-(4- (1-aminocyclobutyl)phenyl)-2- (2-aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) acetamido)-3,3- dimethylbutanoyl)- 4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-10

(2S,4R)-1-((S)-2-(3-(3-(3-(3-(4- (1-aminocyclobutyl)phenyl)-2- (2-aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) propanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-11

(2S,4R)-1-((S)-2-(4-(3-(3-(3-(4- (1-aminocyclobutyl)phenyl)-2- (2-aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) butanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-12

(2S,4R)-1-((S)-2-(5-(3-(3-(3-(4- (1-aminocyclobutyl)phenyl)-2- (2-aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) pentanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-13

(2S,4R)-1-((S)-2-(6-(3-(3-(3-(4- (1-aminocyclobutyl)phenyl)-2- (2-aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) hexanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-14

(2S,4R)-1-((S)-2-(7-(3-(3-(3-(4- (1-aminocyclobutyl)phenyl)-2- (2-aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-15

(2S,4R)-1-((S)-2-(8-(3-(3-(3-(4- (1-aminocyclobutyl)phenyl)-2- (2-aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) octanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-16

(2S,4R)-1-((S)-2-(9-(3-(3-(3-(4- (1-aminocyclobutyl)phenyl)-2- (2-aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) nonanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-17

(2S,4R)-1-((S)-2-(10-(3-(3-(3- (4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) decanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-18

(2S,4R)-1-((S)-2-(11-(3-(3-(3- (4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)propanamido) undecanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-19

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-6]pyridin-5- yl)phenyl)-N-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethyl) propanamide XF067-20

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl) propanamide XF067-21

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(2-(2-(2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy) ethoxy)ethyl)propanamide XF067-22

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(14-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12- tetraoxatetradecyl) propanamide XF067-23

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(17-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15- pentaoxaheptadecyl) propanamide XF067-24

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethyl)propanamide XF067-25

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(3-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)propyl)propanamide XF067-26

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(4-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)butyl)propanamide XF067-27

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(5-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)pentyl)propanamide XF067-28

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(6-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)hexyl)propanamide XF067-29

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(7-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)heptyl)propanamide XF067-30

3-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-N-(8-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)octyl)propanamide XF067-31

(2S,4R)-1-((S)-2-(2-(2-((3-(3- (4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)amino)-2- oxoethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-32

(2S,4R)-1-((S)-2-(3-(3-((3-(3- (4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)amino)-3- oxopropoxy)propanamido)- 3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-33

(2S,4R)-1-((S)-14-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,11- dioxo-6,9-dioxa-3,12- diazatetradecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-34

(2S,4R)-1-((S)-16-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,13- dioxo-7,10-dioxa-3,14- diazahexadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-35

(2S,4R)-1-((S)-17-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,14- dioxo-6,9,12-trioxa-3,15- diazaheptadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-36

(2S,4R)-1-((S)-19-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenyl)-2-(tert-butyl)-4,16- dioxo-7,10,13-trioxa-3,17- diazanonadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-37

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N¹⁶-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-4,7,10,13- tetraoxahexadecanediamide XF067-38

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N¹⁷-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-3,6,9,12,15- pentaoxaheptadecanediamide XF067-39

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N¹⁹-((1S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-4,7,10,13,16- pentaoxanonadecanediamide XF067-40

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N⁴-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)succinamide XF067-41

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N⁵-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)glutaramide XF067-42

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N⁶-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2-yl)adipamide XF067-43

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N⁷-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2- yl)heptanediamide XF067-44

N¹-(3-(3-(4-(1- aminocycIobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N⁸-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)octanediamide XF067-45

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N⁹-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)nonanediamide XF067-46

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N¹⁰-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)decanediamide XF067-47

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-N¹¹-((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1-yl)-3,3-dimethyl-1- oxobutan-2- yl)undecanediamide XF067-48

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)acetamide XF067-49

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-3-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)propanamide XF067-50

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-4-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)butanamide XF067-51

N¹-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-5-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)pentanamide XF067-52

N-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-6-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)hexanamide XF067-53

N-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-7-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)heptanamide XF067-54

N-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-8-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)octanamide XF067-55

N-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-3-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)propanamide XF067-56

N-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-3-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy) propanamid XF067-57

N-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-3-(2-(2-(2-((2- (2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy) ethoxyl)propanamide XF067-58

N-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12-tetraoxapentadecan- 15-amide XF067-59

N-(3-(3-(4-(1- aminocyclobutyl)phenyl)-2-(2- aminopyridin-3-yl)-3H- imidazo[4,5-b]pyridin-5- yl)phenethyl)-1-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)- 3,6,9,12,15- pentaoxaoctadecan-18-amide XF067-84

(2S,4R)-1-((S)-17-((2-(4- amino-1,2,5-oxadiazol-3-yl)-1- ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)-2-(tert-butyl)-4,10- dioxo-6-oxa-3,9,14- triazaheptadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-85

(2S,4R)-1-((S)-18-((2-(4- amino-1,2,5-oxadiazol-3-yl)-1- ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)-2-(tert-butyl)-4,11- dioxo-7-oxa-3,10,15- triazaoctadecanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-86

(2S,4R)-1-((S)-20-((2-(4- amino-1,2,5-oxadiazol-3-yl)-1- ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)-2-(tert-butyl)-4,13- dioxo-6,9-dioxa-3,12,17- triazaicosanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-87

(2S,4R)-1-((S)-21-((2-(4- amino-1,2,5-oxadiazol-3-yl)-1- ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)-2-(tert-butyl)-4,14- dioxo-7,10-dioxa-3,13,18- triazahenicosanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-88

(2S,4R)-1-((S)-23-((2-(4- amino-1,2,5-oxadiazol-3-yl)-1- ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)-2-(tert-butyl)-4,16- dioxo-6,9,12-trioxa-3,15,20- triazatricosanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-89

(2S,4R)-1-((S)-24-((2-(4- amino-1,2,5-oxadiazol-3-yl)-1- ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)-2-(tert-butyl)-4,17- dioxo-7,10,13-trioxa-3,16,21- triazatetracosanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-90

(2S,4R)-1-((S)-27-((2-(4- amino-1,2,5-oxadiazol-3-yl)-1- ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)-2-(tert-butyl)-4,20- dioxo-7,10,13,16-tetraoxa- 3,19,24-triazaheptacosanoyl)- 4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-91

(2S,4R)-1-((S)-30-((2-(4- amino-1,2,5-oxadiazol-3-yl)-1- ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)-2-(tert-butyl)-4,23- dioxo-7,10,13,16,19-pentaoxa- 3,22,27-triazatriacontanoyl)- 4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-92

(2S,4R)-1-((S)-2-(2-(4-((3-((2- (4-amino-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino) butanamido)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-93

(2S,4R)-1-((S)-2-(3-(4-((3-((2- (4-amitio-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino) butanamido)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-94

(2S,4R)-1-((S)-2-(4-(4-((3-((2- (4-amino-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino) butanamido)butanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-95

(2S,4R)-1-((S)-2-(5-(4-((3-((2- (4-amino-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- niethylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino) butanamido)pentanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-96

(2S,4R)-1-((S)-2-(6-(4-((3-((2- (4-amino-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino) butanamido)hexanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-97

(2S,4R)-1-((S)-2-(7-(4-((3-((2- (4-amino-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino) butanamido)heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-98

(2S,4R)-1-((S)-2-(8-(4-((3-((2- (4-amino-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino) butanamido)octanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-99

(2S,4R)-1-((S)-2-(9-(4-((3-((2- (4-amino-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino)butanamido) nonanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-100

(2S,4R)-1-((S)-2-(10-(4-((3-((2- (4-amino-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino) butanamido)decanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-101

(2S,4R)-1-((S)-2-(11-(4-((3-((2- (4-amino-1,2,5-oxadiazol-3- yl)-1-ethyl-4-(3-hydroxy-3- methylbut-1-yn-1-yl)-1H- imidazo[4,5-c]pyridin-7- yl)oxy)propyl)amino) butanamido)undecanamido)-3,3- dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide XF067-102

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(2- (2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethyl) butanamide XF067-103

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(2- (2-(2-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl) butanamide XF067-104

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(2- (2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- yl)amino)ethoxy)ethoxy) ethoxy)ethyl)butanamide XF067-105

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(14- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)-3,6,9,12- tetraoxatetradecyl)butanamide XF067-106

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(17- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)-3,6,9,12,15- pentaoxaheptadecyl) butanamide XF067-107

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(2- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)ethyl)butanamide XF067-108

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(3- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)propyl)butanamide XF067-109

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino-N-(4- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)butyl)butanamide XF067-110

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(5- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)pentyl)butanamide XF067-111

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(6- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)hexyl)butanamide XF067-112

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(7- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)heptyl)butanamide XF067-113

4-((3-((2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-4-(3- hydroxy-3-methylbut-1-yn-1- yl)-1H-imidazo[4,5-c]pyridin- 7-yl)oxy)propyl)amino)-N-(8- ((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4- yl)amino)octyl)butanamide As used herein, in case of discrepancy between the structure and chemical name provided for a particular compound, the structure shall control.

Example 167. AKT Degraders Reduced AKT Protein Levels in BT474 cells (FIG. 1)

BT474 cells were treated with DMSO or indicated compounds at 1 μM, 5 μM or 10 μM for 24 h. The Western blot results showed that various AKT degraders significantly reduced AKT protein levels at 1 μM, while the AKT activity inhibitor GDC0068 had no effect on AKT protein levels but increased pAKT levels.

Example 168. AKT Degraders Reduced AKT Protein Levels in BT474 Cells in a Time-Dependent Manner (FIG. 2).

BT474 cells were treated with DMSO or the indicated compounds at a fixed concentration of 1 μM for 1, 2, 3, 6, 12, or 24 h. The maximum degradation of AKT and inhibition of downstream signaling were observed after 12 h of treatment.

Example 169. AKT Degraders Reduced AKT Protein Levels in BT474 Cells (FIG. 3)

BT474 cells were treated with DMSO or indicated compounds at 1 μM, 5 μM, or 10 μM for 24 h. The Western blot results showed that various AKT degraders significantly reduced AKT protein levels at 1 μM, while the AKT activity inhibitor AZD5363 had no effect on AKT protein levels but increased pAKT levels.

Example 170. AKT Degraders Reduced AKT Protein Levels in BT474 cells (FIG. 4)

BT474 cells were treated with. DMSO or indicated compounds at 0.01 mM, 0.03 μM, 0.1 mM, 0.3 μM, or 1 μM for 24 h. The Western blot results showed that various AKT degraders significantly reduced AKT protein levels at 1 μM, while the AKT activity inhibitor AZD5363 or GDC0068 had no effect on AKT protein levels but increased pAKT levels (FIG. 4A). PC-3 cells, MDA-MB-468 cells, U87MG cells were treated with DMSO or indicated compounds at 1 μM, 3 μM, or 10 μM for 24 h. The Western blot results showed that AKT degrader XF050-21 significantly reduced AKT protein levels in these cell lines, while the AKT activity inhibitor AZD5363 had no effect on AKT protein levels but increased pAKT levels (FIG. 4B).

Example 171. AKT Degraders Reduced AKT Protein Levels in BT474 Cells and PC-3 Cells in a Time-Dependent Manner (FIG. 5)

BT474 cells and PC-3 cells were treated with DMSO or the indicated compounds at a fixed concentration of 1 μM for 1, 2, 4, 8, 12, or 24 h. The maximum degradation of AKT and inhibition of downstream signaling were observed after 24 h of treatment in BT474 cells (FIG. 5A). The maximum degradation of AKT and inhibition of downstream signaling were observed after 12 h of treatment in PC-3 cells (FIG. 5B).

Example 172. AKT Degraders Reduced AKT Protein Levels through E3 Ubiquitin Ligase (FIG. 6)

BT474 Cells were pre-treated with DMSO, VHL-1 (1 mM), MLN4924 (1 μM), MG-132 (20 μM) or AZD5363 (1 μM) for 2 h, before being treated with the 1 μM XF050-21 compounds for 24 h. XF050-21 induced AKT protein degradation is mediated by hijacking the E3 ubiquitin ligase VHL, and it can be rescued by VHL-1, MLN4924, MG-132 or AZD5363 pretreatment.

Example 173: AKT Degraders Inhibit Cancer Cell Proliferation (FIG. 7)

1-3×10³ PC-3 or MDA-MB-468 cells were seeded in 96-well plates in triplicates and treated at the indicated compound concentrations. Cells were monitored using the IncuCyte® live cell imaging system (Essen Bioscience™, Ann Arbor, Mich.) which was placed in a cell culture incubator operated at 37° C. and 5% CO₂. Cell confluence was determined using calculations derived from phase-contrast images. The concentration for 50% of maximal inhibition of cell proliferation (GI50) values were determined by fitting to a standard four-parameter logistic using GraphPad Prism® v5. Graphs depicting the GI₅₀ of AKT degraders XF050-21 for these cancer cell lines are shown in FIGS. 7 .

Example 174. AKT Degraders Inhibit Cancer Cell Proliferation (FIG. 8)

PC-3, MDA-MB-468, HCC₁₁₄₃, and MDA-MB-231 cells were treated with DMSO, AZD5363 or XF050-21 at 0.1 μM, 0.3 μM, 1 μM, 3 μM, or 10 μM for 2 weeks. Cells were stained with Crystal Violet and the Bright field imaging indicated that XF050-21 was more effective in inhibiting cancer cell proliferation than AZD5363 at the same concentration in these cells.

Example 175. Combination Treatment of an AKT Degrader and an mTOR Inhibitor Reduced AKT Protein Levels and Inhibited Downstream Signaling in BT474 Cells (FIG. 9)

BT474 cells were treated with DMSO or indicated compounds combination at indicated concentration for 24 h. The Western blot results showed that the combination treatment of AKT degrader (XF050-21 or XF042-170) and an mTOR inhibitor (Torin1 or Rapamycin) reduced AKT protein levels and inhibited downstream signaling in BT474 cells.

Example 176. XF050-21 was Bioavailable in Mice (FIG. 10)

Standard PK studies were conducted using male Swiss Albino mice. A single 75 mg/kg intraperitoneal (IP) injection of XF050-21 was evaluated. Plasma concentrations of XF050-21 reported at each of the six time points (30 min, 1 h, 2 h, 4 h, 8 h, and 12 h post dosing) are the average values from 3 test animals. There were no abnormal clinical observations noted during the course of the study.

Example 177. AKT Degraders Reduced AKT Protein Levels in PC-3 Cells (FIG. 11)

PC-3 cells were treated with DMSO or indicated compounds at 1 μM for 24 h. The Western blot results showed that various AKT degraders significantly reduced AKT protein levels at 1 μM, while the AKT activity inhibitor ARQ-092 had no effect on reducing AKT protein levels.

Example 178. AKT Degraders Reduced AKT Protein Levels in PC-3 Cells (FIG. 12)

PC-3 cells were treated with DMSO or indicated compounds at 1 μM for 24 h. The Western blot results showed that various AKT degraders significantly reduced AKT protein levels at 1 μM, while the AKT activity inhibitor GSK690693 had no effect on reducing AKT protein levels.

Materials And Methods: General Chemistry Methods

HPLC spectra for all compounds were acquired using an Agilent 1200 Series system with DAD detector. Chromatography was performed on a 2.1×150 mm Zorbax 3005B-C₁₈ ₅ μm column with water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B at a flow rate of 0.4 ml/min. The gradient program was as follows: 1% B (0-1 min), 1-99% B (1-4 min), and 99% B (4-8 min). High-resolution mass spectra (HRMS) data were acquired in positive ion mode using an Agilent G1969A API-TOF with an electrospray ionization (ESI) source. Nuclear Magnetic Resonance (NMR) spectra were acquired on a Bruker DRX-600 spectrometer with 600 MHz for proton (¹H NMR) and 150 MHz for carbon (¹³C NMR); chemical shifts are reported in (δ). Preparative HPLC was performed on Agilent Prep 1200 series with UV detector set to 254 nm. Samples were injected onto a Phenomenex Luna 250×30 mm, 5 μm, C₁₈ column at room temperature. The flow rate was 40 ml/min. A linear gradient was used with 10% (or 50%) of MeOH (A) in H₂O (with 0.1% TFA) (B) to 100% of MeOH (A). HPLC was used to establish the purity of target compounds. All final compounds had >95% purity using the HPLC methods described above.

Cell Culture and Treatment

PC-3, U87MG, HCC₁₁₄₃, MDA-MB-231, MDA-MB-468, BT474 and MCF-7 cell lines were purchased from ATCC. Cell lines were regularly tested in the lab for mycoplasma. All cells were cultured at 37° C. and 5% CO2. PC-3, U87MG, MDA-MB-231, MCF-7 and BT474 cells were cultured in 1× DMEM (Coming, 10-013-CV) with 10% fetal bovine serum (Atlanta Biologicals S11150) and 1× Penicillin/Streptomycin. HCC1143 cells were cultured in RPMI (Corning, 10-040-CV) medium with 10% fetal bovine serum (Atlanta Biologicals S11150) and1×0 Penicillin/Streptomycin, Cells were split using 0.05% or 0.25% trypsin (Corning 25-051-Cl or 25-053-Cl, respectively) before they reached full confluence and media was changed every 3-4 days. Cells were treated with compounds individually at different concentrations for 24 hrs. Cells were treated with DMSO, VHL, or PML alone as controls.

Immunoblotting

Cells were lysed in 2× sample buffer (25 mM Tris-HCl at pH 6.8, 10% βME, 2% SDS, 20% glycerol, 0.05% Bromophenol Blue, 8 M urea). Protein lysates were loaded into 4-12% Bis-Tris gels and resolved by electrophoresis. Samples were then blotted on PVDF membrane (Millipore IPVH00010) using the wet transfer technique (Invitrogen). Membranes were blocked in 5% milk-TBST for 1 hour, washed in TBST for 10 min, and incubated in primary antibody in 5% milk-TBST or 5% BSA-TBST at 4° C., for 16 h. Membranes were rinsed (3×6 min) in TBST and incubated in horseradish peroxidase-conjugated secondary antibodies in 5% milk-TBST for I hour and rinsed again in TBST (3×6 min). Membranes were visualized using the chemiluminescence system (Thermo 34080, 37075) on autoradiography film (Denville E3018). Primary Antibodies: β-actin (Sigma A5316), p-AKT (Ser473 CST-9721), total AKT (CST-9272), p-S6 (Ser240/244, CST-5364), p-PRAS40 (Thr246, CST-2997). Secondary Antibodies: Mouse (Thermo 31432), Rabbit (Thermo 31460).

Cell Viability Assay

Cells were cultured for 12-17 days in the presence of different compounds. Media with compound was replenished every two days. At the end of the experiment, media was aspirated and viable cells were stained with 0.5% crystal violet dye.

Proliferation and Apoptosis Assays

Experiments were carried out irr 96-well plates in triplicates. A total of 1-3 >10³ cells per well were grown in the presence of 1 μM of AZD5363 (Selleckchem), 1 μM of selected degrader compounds. Cells were then monitored for 3-4 days using the IncuCyte live cell imaging system (Essen BioScience, Ann Arbor, Mich., USA), which was placed in a cell culture incubator operated at 37° C. and 5% CO₂. Cell confluence was determined using calculations derived from phase-contrast images. For measurement of cell death DRAQ7 (Cell Signaling #7406) at 1.5 μM was included in the medium and apoptotic red counts were measured in IncuCyte™ FLR automated incubator microscope.

Xenograft Studies

Thirty male immunocompromised nuinu mice (The Jackson Laboratory) was engrafted with PC-3 human prostate cancer cells that have never been passed through animals and was used under blood-born pathogen laboratory procedures, After tumor volumes reach ˜100 mm³, 3 treatment arms (10 animals per group) were administrated with vehicle control, AZD5363, or a selected degrader compound daily for 3-4 weeks via intraperitoneal (IP) injections. Tumor volume was calculated as follows: tumor size (mm³) (longer measurement×shorter measurement²)×0.5. Tumor sizes were recorded every other day over the course of the studies. Engraftment and monitoring of tumor growth and toxicity in mice were be performed. Treatments would be discontinued if toxicity or distress is encountered, All procedures involving mice and experimental protocols (LA13-00024) were approved by the Institutional Animal Care and Use Committee (IACUC) of Icahn School of Medicine at Mount Sinai (ISMMS).

Immunohistochemistry

Paraffin sections were dewaxed as previously described. If necessary, antigen retrieval was performed, typically, the sections were boiled in 0.01M sodium citrate, pH 6.0, 0.05% Tween-20 twice for 10 min, and then cooled at room temperature for 20 min. After that, the sections were washed with dd H₂O for 3 times of 5 min each and then washed with PBS for 5 min. HRP conjugated secondary antibody was used to detect the signal. Endogenous HRP was blocked with 3% H₂O in PBS or methanol for 10 min. Then the slide was washed in PBS for 3 times of 5 mins each. At this time, the section on slide was circled with a PAP pen. For cryosections, the sections were warmed from −80° C. freezer to room temperature and dried at room temperature for 30 mins or 15 mins at 50° C. Then sections were fixed in ice-cold acetone for 5 min on ice, and then air dried at room temperature for 30 mins, followed by washing with 1× PBS for 5 minsoAfterwards, the endogenous HRP was blocked with 3% H₂O₂ if necessary. The sections were washed again with PBS for 3 times of 5 mins each before circled with a PAP pen.

Statistics

No statistical methods were used to determine sample size, and experiments were not randomized. The experimenters were not blinded. Aside from traditional Mann-Whitney (non-parametric), SpeafliIan correlation test (non-parametric), student t-tests (parametric) to compare two data sets, and Chi-squared test (non-parametric), parametric statistical methods were used in order to make appropriate multiple comparisons of repeated measures of data (following 1-way or 2-way ANOVA). Graphpad Prism was used to make these simple predetermined statistical comparisons. Tukey's Multiple Comparisons Correction: Used for making all possible pairwise comparisons in a data set. Dunnett's Multiple Comparisons Correction: Used for comparing all samples to a control sample, but not for comparing the non-control samples to one another. Sidak's Multiple Comparisons Correction: Used when specific multiple comparisons are pre-selected. Fischer's Exact Test: Used to analyze items in a contingency table.

Other Embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

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1.-112. (canceled)
 113. A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3;

wherein A, B and X are independently N or CR³, Y is CH₂, CO, SO, SO₂, CR⁴R⁵, CONR⁴, or SO₂NR⁴, E is NH, NR⁶, O, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, OR⁶, SR⁶, NR⁶R⁷, CN, NO₂, (CR⁶R⁷)_(m)NR⁸R⁹, (CR⁶R⁷)_(m)C(O)R⁸, (N R⁶R⁷)_(m)NR⁸R⁹, (NR⁶R⁷)_(m)C(O)R⁸, COR⁶, CO₂R⁶, CONR⁶R⁷, NR⁶COR⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, SOR⁶, SO₂R⁶, SO₂NR⁶R⁷, (CR⁶R⁷)_(m)-aryl, or (CR⁶R⁷)_(m)-heteroaryl, Z¹-Z² is CR¹⁰═CH, N═CH, or CR¹⁰═N, R¹ is hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, aryl, C₁-C₈ alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl, R², R³, and R⁴ are independently hydrogen, halogen, amino, C₁-C₈ alkylamino, arylamino, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkoxyalkyl, R⁶, R⁷, R⁸, and R⁹ are independently H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₂-C₈ alkenyl, C₂-C₈ alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl, R⁶ and R⁷, R⁸ and R⁹ can independently form 4-8 membered alkyl or heterocyclyl rings, R¹⁰ is hydrogen, halogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, m=0-8 and n=0-8; the degradation disruption tag comprises FORMULA 6;

wherein R¹ and R² are independently hydrogen, C₁-C₈ alkyl, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ heterocyclyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl; and the linker comprises FORMULA A;

wherein X is C═O or CH₂, Y is C═O or CH₂, and n is 0-15; and pharmaceutically acceptable salts thereof.
 114. The bivalent compound of claim 113, wherein in Formula 3, A is CR³; B is N; X is N; Y is CO; E is C₃-C₈ heterocyclyl; Z¹-Z² is CR¹⁰═CH; R¹ is aryl or haloaryl; R² is hydrogen; R³ is amino; R¹⁰ is hydrogen; and n=2.
 115. The bivalent compound of claim 113, wherein in Formula 6, R¹ is C₁-C₈ alkyl and R² is hydrogen.
 116. The bivalent compound of claim 113, wherein in Formula A, X is C═O and Y is C═O.
 117. The bivalent compound of claim 114, wherein in Formula 3, E is piperazinyl.
 118. The bivalent compound of claim 114, wherein in Formula 3, R¹ is 4-chlorophenyl.
 119. The bivalent compound of claim 115, wherein in Formula 6 R¹ is tert-butyl.
 120. The bivalent compound of claim 116, wherein in Formula A, n is 9 or
 10. 121. 4-amino-N-((S)-1-(4-chlorophenyl)-3-(4-(11-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecanoyl)piperazin-1-yl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (XF050-21), and pharmaceutically acceptable salts thereof.
 122. 4-amino-N-((S)-1-(4-chlorophenyl)-3-(4-(12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoyl)piperazin-1-yl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (XF050-143), and pharmaceutically acceptable salts thereof.
 123. A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3;

wherein A, B and X are independently N or CR³, Y is CH₂, CO, SO, SO₂, CR⁴R⁵, CONR⁴, or SO₂NR4, E is NH, NR⁶, O, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocyclyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, OR⁶, SR⁶, NR⁶R⁷, CN, NO₂, (CR⁶R⁷)_(m)NR⁸R⁹, (CR⁶R⁷)_(m)C(O)R⁸, (N R⁶R⁷)_(m)NR⁸R⁹, (NR⁶R⁷)_(m)C(O)R⁸, COR⁶, CO₂R⁶, CONR⁶R⁷, NR⁶COR⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, SOR⁶, SO₂R⁶, SO₂NR⁶R⁷, (CR⁶R⁷)_(m)-aryl, or (CR⁶R⁷)_(m)-heteroaryl, Z¹-Z² is CR¹⁰═CH, N+CH, or CR¹⁰═N, R¹ is hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, aryl, C₁-C₈ alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl, R², R³, and R⁴ are independently hydrogen, halogen, amino, C₁-C₈ alkylamino, arylamino, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkoxyalkyl, R⁶, R⁷, R⁸, and R⁹ are independently H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₂-C₈ alkenyl, C₂-C₈ alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl, R⁶ and R⁷, R⁸ and R⁹ can independently form 4-8 membered alkyl or heterocyclyl rings, R¹⁰is hydrogen, halogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkoxyalkyl, m=0-8; and n=0-8; the degradation disruption tag comprises FORMULA 5A;

wherein V, W and X are independently selected from CR² and N; Y is selected from CO, CH₂, and N═N; Z is selected from CH₂, NH and O; and R¹ and R² are independently selected from hydrogen, halogen, cyano, nitro, and C₁-C₅ alkyl; and the linker comprises FORMULA B;

wherein X is C═O or CH₂, Y is C═O or CH₂, m is 0-15, n is 0-6, and o is 0-15, and pharmaceutically acceptable salts thereof.
 124. The bivalent compound of claim 123, wherein in Formula 3, A is CR³; B is N; X is N; Y is CO; E is C₃-C₈ heterocyclyl; Z¹-Z² is CR¹⁰═CH; R¹ is aryl or haloaryl; R² is hydrogen; R³ is amino; R¹⁰ is hydrogen; and n=2.
 125. The bivalent compound of claim 123, wherein in Formula 5A, R¹ and R² are each hydrogen; Y is CO; X, V and W are each CR²; and Z is NH.
 126. The bivalent compound of claim 123, wherein in Formula B, X is C═O, m is 1, n is 4, o is 0 and Y is CH₂.
 127. The bivalent compound of claim 124 wherein in Formula 3, E is piperazinyl.
 128. The bivalent compound of claim 124 wherein in Formula 3, R¹ is 4-chlorophenyl.
 129. 4-amino-N-((1S)-1-(4-chlorophenyl)-3-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (XF050-33) and pharmaceutically acceptable salts thereof.
 130. A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3C;

the degradation disruption tag comprises FORMULA 6;

wherein R¹ and R² are independently hydrogen, C₁-C₈ alkyl, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ heterocyclyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl; and the linker comprises FORMULA C;

wherein X is C═O or CH₂, Y is C═O or CH₂, R is —CH₂—, —CF₂—, —CH(C₁₋₃ alkyl)-, —C(C₁₋₃ alkyl)(C₁₋₃ alkyl)-, —CH═CH—, —C(C₁₋₃ alkyl)=C(C₁₋₃ alkyl)- , —C═C—, —O—, —NH—, —N(C₁₋₃ alkyl)-, —C(O)NH—, —C(O)N(C₁₋₃ alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring, m is 0-15, and n is 0-15, and pharmaceutically acceptable salts thereof.
 131. The bivalent compound of claim 130, wherein in Formula 6, R¹ and R² are each C₁-C₈ alkyl.
 132. The bivalent compound of claim 130, wherein in Formula C, X is CH₂, Y is C═O, R is —C(O)NH—, m is 1, and n is
 10. 133. The bivalent compound of claim 131, wherein in Formula 6, R¹ is tert-butyl and R² is methyl.
 134. N¹-(2-(((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)ethyl)-N¹²-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)dodecanediamide (XF050-98), and pharmaceutically acceptable salts thereof.
 135. A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3C;

the degradation disruption tag comprises FORMULA 5A;

wherein V, W, and X are independently selected from CR² and N; Y is selected from CO, CH₂, and N═N; Z is selected from CH₂, NH and O; and R¹ and R² are independently selected from hydrogen, halogen, cyano, nitro, and C₁-C₅ alkyl; and the linker comprises FORMULA C;

wherein X is C═O or CH₂, Y is C═O or CH₂, R is —CH₂—, —CF₂—, —CH(C₁₋₃ alkyl)-, —C(C₁₋₃ alkyl)(C₁₋₃ alkyl)-, —CH═CH—, —C(C₁₋₃ alkyl)=C(C₁₋₃ alkyl)-, —C═C—, —O—, —NH—, —N(C₁₋₃ alkyl)-, —C(O)NH—, —C(O)N(C₁₋₃ alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring, m is 0-15, and n is 0-15, and pharmaceutically acceptable salts thereof.
 136. The bivalent compound of claim 135, wherein in Formula 5A, R¹ and R² are each hydrogen, Y is CO, X, V and W are each CR², and Z is NH.
 137. The bivalent compounds of claim 135, wherein in Formula C, X is CH₂, Y is CH₂, R is —C(O)NH—, m is 1 and n is
 7. 138. 3-(((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)propanamide (XF042-170), and pharmaceutically acceptable salts thereof.
 139. A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3J;

the degradation disruption tag comprises FORMULA 6;

wherein R¹ and R² are independently hydrogen, C₁-C₈ alkyl, C₁-C₈ alkoxyalkyl, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ heterocyclyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl; and the linker comprises FORMULA C;

wherein X is C═O or CH₂, Y is C═O or CH₂, R is —CH₂—, —CF₂—, —CH(C₁₋₃ alkyl)-, —C(C₁₋₃ alkyl)(C₁₋₃ alkyl)-, —CH═CH—, —C(C₁₋₃ alkyl)=C(C₁₋₃ alkyl)-, —C═C—, —O—, —NH—, —N(C₁₋₃ alkyl)-, —C(O)NH—, —C(O)N(C₁₋₃ alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring, m is 0-15, and n is 0-15, and pharmaceutically acceptable salts thereof.
 140. The bivalent compound of claim 139, wherein in Formula 6, R¹ is C₁-C₈ alkyl and R² is hydrogen or C₁-C₈ alkyl.
 141. The bivalent compounds of claim 139, wherein in Formula C, X is CH₂, Y is C═O, R is —C(O)NH—, m is 1 and n is
 10. 142. (2S,4R)-1-((S)-2-(11-(3-(3-(3-(4-(1-aminocyclobutyl)phenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)propanamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (XF067-18) and pharmaceutically acceptable salts thereof. 